Substituted picolinamides as MAO-B inhibitors useful for treating obesity

ABSTRACT

The invention provides novel compounds of formula I: 
                         
that are monoamine oxidase-B inhibitors, which can be useful in treating obesity, diabetes, and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias, high blood pressure, and insulin resistance).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. ProvisionalApplication No. 60/698,867 filed Jul. 13, 2005, now pending, which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides compounds and pharmaceutical compositionsthereof and methods of using the same for treating obesity, diabetes,and/or cardiometabolic disorders (e.g., hypertension, dyslipidemias,high blood pressure, and insulin resistance).

BACKGROUND OF THE INVENTION

Lazabemide is a monoamine oxidase (MAO) inhibitor that was developed forthe treatment of neurological disorders such as Parkinson's disease anddementia. MAO is an enzyme responsible for metabolizing biogenicmonoamines including serotonin, dopamine, histamine, andphenylethylamine. By inhibiting MAO located in the central nervoussystem (CNS), MAO inhibitors and their analogues increase theconcentration of monoamines present within the brain synapses. Thisenhances monoamine-mediated neurotransmission, effectively treatingneurological disorders such as Parkinson's disease and depression.

MAO enzymes are also located in a number of peripheral (non-CNS)tissues, including adipocytes; the cells that comprise body fat. Thefunction of MAO enzymes in adipocytes has not been established.Currently, the only approved clinical use of L-selegiline and other MAOinhibitors is for the treatment of neurological disorders such asParkinson's disease and depression.

Obesity is associated with an increase in the overall amount of adiposetissue (i.e., body fat), especially adipose tissue localized in theabdominal area. Obesity has reached epidemic proportions in the UnitedStates. The prevalence of obesity has steadily increased over the yearsamong all racial and ethnic groups. According to the United StatesSurgeon General, 61% of the adult population and 14% of children areobese or overweight. Forty four million Americans are obese, with anadditional eighty million deemed medically overweight. Obesity isresponsible for more than 300,000 deaths annually, and will soonovertake tobacco usage as the primary cause of preventable death in theUnited States. Obesity is a chronic disease that contributes directly tonumerous dangerous co-morbidities, including type 2 diabetes,cardiovascular disease, inflammatory diseases, premature aging, and someforms of cancer. Type 2 diabetes, a serious and life-threateningdisorder with growing prevalence in both adult and childhoodpopulations, is currently the 7^(th) leading cause of death in theUnited States. Since more than 80% of patients with type 2 diabetes areoverweight, obesity is the greatest risk factor for developing type 2diabetes. Increasing clinical evidence indicates that the best way tocontrol type 2 diabetes is to reduce weight.

The most popular over-the counter drugs for the treatment of obesity,phenylpropanolamine and ephedrine, and the most popular prescriptiondrug, fenfluramine, were removed from the marketplace as a result ofsafety concerns. Drugs currently approved for the long-term treatment ofobesity fall into two categories: (a) CNS appetite suppressants such assibutramine and (b) gut lipase inhibitors such as orlistat. CNS appetitesuppressants reduce eating behavior through activation of the ‘satietycenter’ in the brain and/or by inhibition of the ‘hunger center’ in thebrain. Gut lipase inhibitors reduce the absorption of dietary fat fromthe gastrointestinal (GI) tract. Although sibutramine and orlistat workthrough very different mechanisms, they share in common the same overallgoal of reducing body weight secondary to reducing the amount ofcalories that reach the systemic circulation. Unfortunately, theseindirect therapies produce only a modest initial weight loss(approximately 5% compared to placebo) that is usually not maintained.After one or two years of treatment, most patients return to or exceedtheir starting weight. In addition, most approved anti-obesitytherapeutics produce undesirable and often dangerous side effects thatcan complicate treatment and interfere with a patient's quality of life.

The lack of therapeutic effectiveness, coupled with the spiralingobesity epidemic, positions the ‘treatment of obesity’ as one of thelargest and most urgent unmet medical needs. There is, therefore, a realand continuing need for the development of improved medications thattreat obesity.

MAO-B inhibitors such as lazabemide have been clinically useful in thetreatment of CNS disorders. They have now unexpectedly been discoveredto also have anti-obesity activity. Even more surprising is that theanti-obesity activity effects of MAO-B inhibitors are mediated via aperipheral (i.e., non-CNS) mechanism. This new discovery provides anovel approach for the treatment of obesity. Moreover, if the CNSeffects of these compounds can be reduced, their peripherally mediatedanti-obesity properties should provide therapeutic agents with greatersafety. It has, as a result, become highly desirable to find MAO-Binhibitors with limited or no CNS effects. Compounds of this sort areexpected to be useful in treating obesity and the variety ofco-morbidities to which it contributes.

SUMMARY OF THE INVENTION

Accordingly, in an aspect, the present invention provides novel MAO-Binhibitors or stereoisomers or pharmaceutically acceptable salts thatare useful to treat obesity, diabetes, and/or cardiometabolic disorders(e.g., hypertension, dyslipidemias, high blood pressure, and insulinresistance).

In another aspect, the present invention provides novel pharmaceuticalcompositions, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer or pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides novel methods fortreating obesity, diabetes, and/or cardiometabolic disorders (e.g.,hypertension, dyslipidemias, high blood pressure, and insulinresistance), comprising: administering to a patient in need thereof atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer or pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides novel methods fortreating CNS disorders, comprising: administering to a patient in needthereof a therapeutically effective amount of at least one of thecompounds of the present invention or a stereoisomer or pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides processes forpreparing novel compounds.

In another aspect, the present invention provides novel compounds orstereoisomers or pharmaceutically acceptable salts for use in therapy.

In another aspect, the present invention provides the use of novelcompounds for the manufacture of a medicament for the treatment ofobesity, diabetes, and/or cardiometabolic disorders.

In another aspect, the present invention provides the use of novelcompounds for the manufacture of a medicament for the treatment of CNSdisorders.

These and other aspects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed compounds or stereoisomers orpharmaceutically acceptable salts thereof are expected to be effectiveMAO-B inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the unexpected finding that an MAO-Binhibitor is capable of reducing the amount of adipose tissue (i.e.,body fat) in a warm-blooded mammal. This finding was unexpected becausebody fat can be reduced despite little, if any, concomitant reduction infood intake.

In an embodiment, the present invention provides novel compound AA or astereoisomer or pharmaceutically acceptable salt thereof:

wherein: Q is C═O or SO₂; A, A¹, A², A³, and A⁴ are selected from CA⁵,N⁺—O⁻, or N; and A⁵ (independently at each occurrence), R, R¹, and R²are all independently selected from H and a group capable of reducing orlimiting the CNS activity of compound A; and,

provided that at least one of the A groups is other than H, halogen,nitro, NH₂, OH, OC₁₋₆ alkyl, C₁₋₆ alkyl, phenyl, and benzyloxy.

[1] In another embodiment, the present invention provides a novelcompound of formula I, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

A, A¹, A², A³, and A⁴, are independently selected from CH, CX, CY, N,and N⁺—O⁻, provided that from 0-1 is N⁺—O⁻;

R, at each occurrence, is independently selected from H and C₁₋₆ alkyl;

R¹ is selected from H and C₁₋₆ alkyl;

R² is selected from H and C₁₋₆ alkyl;

Q is selected from C═O and SO₂;

X is selected from H, OR³, NR³Z, OZ, SZ, SO₂OR³, SO₂NR³R⁴, CO₂R³,CONR³R⁴, PO(OR³)₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole,(CH₂)_(m)CO₂R, (CH₂)_(m)CONR₂, (CH₂)_(m)CN, NR—C₂₋₄ alkenyl, NRSO₂CH₃,NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-tetrazole, CH₂-aryl, O(CH₂)_(n)-biphenyl,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl,O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole, NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl-O(CH₂)_(n)-tetrazole, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole,O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole,O(CH₂)_(n)-heteroarylO (CH₂)_(n)CN,O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X² and tetrazoleis substituted with 0-1 R;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₁₋₄ alkyloxy, fluoro-C₁₋₄ alkyloxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halogen, CF₃, nitro, —CN, CON(R)₂, and SO₂N(R)C₁₋₄alkyl;

Y is selected from H, OR³, NR³Z, OZ, SZ, SO₂OR³, SO₂NR³R⁴, CO₂R³,CONR³R⁴, PO(OR³)₂, (CH₂)_(m)-tetrazole, O(CH₂)_(n)-tetrazole, C₁₋₄alkyl, halogen, CF₃, nitro, —CN, CON(R)₂, SO₂N(R)C₁₋₄alkyl and NHSO₂R;

provided that when Q is C═O and A, A¹, A², A³, and A⁴ are other thanN⁺—O⁻ then at least one of X and Y is present and is other than H orOR³;

Z, at each occurrence, is independently selected from H, C₁₋₆ alkyl,(CH₂)_(n)CO₂R³, CH₂CH═CHCO₂R³, (CH₂)_(n)CN, (CH₂)_(n)CONR³R⁴,CH₂CH═CHCN, CH₂CH═CHCON(R³)₂, (CH₂)_(n)PO(OR³)₂, (CH₂)_(n)SO₃R³,(CH₂)_(n)N(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻;

G⁻ is a counterion;⁻

R³, at each occurrence, is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, and aryl-C₁₋₁₆ alkyl-;

R⁴, at each occurrence, is independently selected from H, C₁₋₆ alkyl,phenyl, and CH(L)CO₂R³;

L is selected from H, C₁₋₆ alkyl, —(CH₂)_(m)-phenyl, —(CH₂)_(n)—O—C₁₋₆alkyl, and —(CH₂)_(n)—S—C₁₋₆ alkyl;

m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

n, at each occurrence, is independently selected from 1, 2, 3, and 4;and,

p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11.

In another embodiment, the compounds of the present invention have from0-1 acid functionalities.

[2] In another embodiment, the present invention provides a novelcompound of formula Ia, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

A, A¹, and A³, are independently selected from CH, CX, CY, N, and N⁺—O⁻,provided that from 0-1 is N⁺—O⁻;

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

R² is selected from H and C₁₋₄ alkyl;

X is selected from H, OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, NHSO₂R,(CH₂)_(n)CONR₂, (CH₂)_(n)CN, NR—C₂₋₄ alkenyl, NRSO₂CH₃, CH₂-aryl,O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²;

provided that the heteroaryl in X is other than tetrazole;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂,and SO₂N(R)C₁₋₄alkyl;

Y is selected from SO₂OR³, CO₂R³, PO(OR³)₂, (CH₂)_(m)-tetrazole,O(CH₂)_(n)-tetrazole, SO₂N(R)C₁₋₄alkyl, and NHSO₂R;

Z is selected from H, C₁₋₄ alkyl, (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂,(CH₂)_(n)N(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻;

G⁻ is selected from Cl⁻ and Br⁻;

R³, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, and benzyl;

R⁴, at each occurrence, is independently selected from H, C₁₋₄ alkyl,phenyl, and CH(L)CO₂R³; and,

L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.

[2a] In another embodiment, the present invention provides a novelcompound of formula Ia₁, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

Y is selected from OR³ and O(CH₂)_(n)CO₂R³; and,

Z is selected from (CH₂)_(n)CO₂R³, CH₂CH═CHCO₂R³, CH₂═CHCON(R³)₂,(CH₂)_(n)CONR³R⁴, (CH₂)_(n)PO(OR³)₂, and (CH₂)_(n)SO₃R³.

[3] In another embodiment, the present invention provides a novelcompound of formula Ia, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

A, A¹, and A³, are independently selected from CH, CX, CY, N, and N⁺—O⁻,provided that from 0-1 is N⁺—O⁻;

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

R² is selected from H and C₁₋₄ alkyl;

X is selected from SO₂OR³, PO(OR³)₂, (CH₂)_(m)-tetrazole,O(CH₂)_(n)-tetrazole, (CH₂)_(m)CO₂R, NR(CH₂)_(n)CO₂R,NR(CH₂)_(n)-tetrazole, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,O(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole,O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R,O(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole,O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,NR(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole,NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-NR—C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl-NR(CH₂)_(n-)tetrazole,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl-O(CH₂)_(n-)tetrazole,NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R,O(CH₂)_(n)-heteroaryl-C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole,O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole,O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n-)tetrazole,NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X² and tetrazoleis substituted with 0-1 R;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂,and SO₂N(R)C₁₋₄alkyl;

Y is selected from H, OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, C₁₋₄ alkyl,halogen, CF₃, nitro, —CN, CON(R)₂, SO₂N(R)C₁₋₄alkyl, and NHSO₂R;

provided that when A, A¹, and A³ are other than N⁺—O⁻, then at least oneof X and Y is present and is other than H or OR³;

Z is selected from H, C₁₋₄ alkyl, (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂,(CH₂)_(n)N(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻;

G⁻ is selected from Cl⁻ and Br⁻;

R³, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, and benzyl;

R⁴, at each occurrence, is independently selected from H, C₁₋₄ alkyl,phenyl, and CH(L)CO₂R³; and,

L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.

[3a] In another embodiment, the present invention provides a novelcompound of formula Ia₁, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

Z is selected from (CH₂)_(n)CO₂R³, CH₂CH═CHCO₂R³, CH₂═CHCON(R³)₂,(CH₂)_(n)CONR³R⁴, (CH₂)_(n)PO(OR³)₂, and (CH₂)_(n)SO₃R³

[4] In another embodiment, the present invention provides a novelcompound of formula Ib, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

A and A¹, are independently selected from CH and N;

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

R² is selected from H and C₁₋₄ alkyl;

X is selected from H, OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, NHSO₂R,(CH₂)_(n)CONR₂, (CH₂)_(n)CN, NR—C₂₋₄ alkenyl, NRSO₂CH₃, CH₂-aryl,O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²;

provided that the heteroaryl in X is other than tetrazole;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂,and SO₂N(R)C₁₋₄alkyl;

Y is selected from SO₂OR³, CO₂R³, PO(OR³)₂, (CH₂)_(m)-tetrazole,O(CH₂)_(n)-tetrazole, SO₂N(R)C₁₋₄alkyl and NHSO₂R;

Z is selected from H, C₁₋₄ alkyl, (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂,(CH₂)_(n)N(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻;

G⁻ is selected from Cl⁻ and Br⁻;

R³, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, and benzyl;

R⁴, at each occurrence, is independently selected from H, C₁₋₄ alkyl,phenyl, and CH(L)CO₂R³; and,

L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.

[5] In another embodiment, the present invention provides a novelcompound of formula Ib, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

A and A¹, are independently selected from CH and N;

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

R² is selected from H and C₁₋₄ alkyl;

X is selected from SO₂OR³, PO(OR³)₂, (CH₂)_(m)-tetrazole,O(CH₂)_(n)-tetrazole, (CH₂)_(m)CO₂R, NR(CH₂)_(n)CO₂R, NR(CH₂)-tetrazole,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,O(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)tetrazole, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,O(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂) m-tetrazole,O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R,O(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-arylO(CH₂)_(n)-tetrazole, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole,O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,NR(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)-tetrazole,NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-NR—C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)-tetrazole,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R, NR(CH₂)-aryl-O(CH₂)_(n)-tetrazole,NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂, O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R,O(CH₂)_(n)-heteroaryl-C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole, O(CH₂)n-heteroaryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R,O(CH₂)_(n)-heteroaryl-O—C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-heteroarylO(CH₂)_(n)-tetrazole,O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)-tetrazole,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)-tetrazole,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)-tetrazole,NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X² and tetrazoleis substituted with 0-1 R;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂,and SO₂N(R)C₁₋₄alkyl;

Y is selected from H, OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, C₁₋₄ alkyl,halogen, CF₃, nitro, —CN, CON(R)₂, SO₂N(R)C₁₋₄alkyl and NHSO₂R;

provided that when A, A¹, and A³ are other than N⁺—O⁻, then at least oneof X and Y is present and is other than H or OR³;

Z is selected from H, C₁₋₄ alkyl, (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂,(CH₂)_(n)N(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻;

G⁻ is selected from Cl⁻ and Br⁻;

R³, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, and benzyl;

R⁴ at each occurrence, is independently selected from H, C₁₋₄ alkyl,phenyl, and CH(L)CO₂R³; and,

L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.

[6] In another embodiment, the present invention provides a novelcompound of formula Ic, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

A and A¹, are independently selected from CH and N;

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

R² is selected from H and C₁₋₄ alkyl;

X is selected from H, OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, NHSO₂R,(CH₂)_(n)CONR₂, (CH₂)_(n)CN, NR—C₂₋₄ alkenyl, NRSO₂CH₃, CH₂-aryl,O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²;

provided that the heteroaryl in X is other than tetrazole;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂,and SO₂N(R)C₁₋₄alkyl;

Z is selected from H, C₁₋₄ alkyl, (CH₂)_(n)N(R³)₂, and(CH₂)_(n)N⁺(R³)₃G⁻;

G⁻ is selected from Cl⁻ and Br⁻;

R³ at each occurrence, is independently selected from H, C₁₋₄ alkyl, andbenzyl;

R⁴ at each occurrence, is independently selected from H, C₁₋₄ alkyl, andCH(L)CO₂R³; and,

L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.

[7] In another embodiment, the present invention provides a novelcompound of formula Id, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

A is CH or N;

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

R² is selected from H and C₁₋₄ alkyl;

X is selected from H, OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, NHSO₂R,(CH₂)_(n)CONR₂, (CH₂)_(n)CN, NR—C₂₋₄ alkenyl, NRSO₂CH₃, CH₂-aryl,O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²;

provided that the heteroaryl in X is other than tetrazole;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂,and SO₂N(R)C₁₋₄alkyl;

Z is selected from H, C₁₋₄ alkyl, (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂,(CH₂)_(n)N(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻;

G⁻ is selected from Cl⁻ and Br⁻;

R³ at each occurrence, is independently selected from H, C₁₋₄ alkyl, andbenzyl;

R⁴ at each occurrence, is independently selected from H, C₁₋₄ alkyl, andCH(L)CO₂R³; and,

L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.

[8] In another embodiment, the present invention provides a novelcompound of formula Ie, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein:

R, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R¹ is selected from H and C₁₋₄ alkyl;

R² is selected from H and C₁₋₄ alkyl;

X is selected from H, OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, NHSO₂R,(CH₂)_(n)CONR₂, (CH₂)_(n)CN, NR—C₂₋₄ alkenyl, NRSO₂CH₃, CH₂-aryl,O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂5 NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²;

provided that the heteroaryl in X is other than tetrazole;

X², at each occurrence, is independently selected from H, OR, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂,and SO₂N(R)C₁₋₄alkyl;

Z is selected from H, C₁₋₄ alkyl, (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂,(CH₂)_(n)N(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻;

Y is selected from H, OR³, NR³Z, and NHSO₂R;

provided that at least one of X and Y is other than H or OR³;

G⁻ is selected from Cl⁻ and Br⁻;

R³ at each occurrence, is independently selected from H, C₁₋₄ alkyl, andbenzyl;

R⁴ at each occurrence, is independently selected from H, C₁₋₄ alkyl, andCH(L)CO₂R³; and,

L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a stereoisomer or pharmaceutically acceptable saltthereof.

In another embodiment, the present invention provides a novel method fortreating a disease, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a stereoisomer or pharmaceutically acceptable salt thereof,wherein the disease is selected from obesity, diabetes, cardiometabolicdisorders, and a combination thereof.

In another embodiment, the cardiometabolic disorder is selected fromhypertension, dyslipidemias (e.g., undesirable blood lipid levels,elevated cholesterol levels, and lowered LDL levels), high bloodpressure, and insulin resistance.

In another embodiment, the present invention provides a novel method fortreating a co-morbidity of obesity, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a stereoisomer or pharmaceuticallyacceptable salt thereof.

In another embodiment, the co-morbidity is selected from diabetes,Metabolic Syndrome, dementia, and heart disease.

In another embodiment, the co-morbidity is selected from hypertension;gallbladder disease; gastrointestinal disorders; menstrualirregularities; degenerative arthritis; venous statis ulcers; pulmonaryhypoventilation syndrome; sleep apnea; snoring; coronary artery disease;arterial sclerotic disease; pseudotumor cerebri; accident proneness;increased risks with surgeries; osteoarthritis; high cholesterol; and,increased incidence of malignancies of the ovaries, cervix, uterus,breasts, prostrate, and gallbladder.

In another embodiment, the present invention provides a novel method fortreating a CNS disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention or a stereoisomer or pharmaceutically acceptable salt thereof.

In another embodiment, the CNS disorder is selected from acute andchronic neurological disorders, cognitive disorders, and memorydeficits. Examples of these disorders include chronic or traumaticdegenerative processes of the nervous system, which include Alzheimer'sdisease, other types of dementia, minimal cognitive impairment, andParkinson's disease. Other examples of CNS disorders include psychiatricdiseases, which include depression, anxiety, panic attack, socialphobia, schizophrenia, and anorexia. Further examples of CNS disordersinclude withdrawal syndromes induced by alcohol, nicotine and otheraddictive drugs. Additional examples of CNS disorders includeneuropathic pain and neuroinflamatory diseases (e.g., multiplesclerosis).

In another embodiment, the present invention also provides a method ofpreventing or reversing the deposition of adipose tissue in a mammal bythe administration of a MAO-B inhibitor. By preventing or reversing thedeposition of adipose tissue, MAO-B inhibitors are expected to reducethe incidence or severity of obesity, thereby reducing the incidence orseverity of associated co-morbidities.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides the use ofcompounds of the present invention for the manufacture of a medicamentfor the treatment of obesity, diabetes, cardiometabolic disorders, and acombination thereof.

In another embodiment, the present invention provides the use of novelcompounds for the manufacture of a medicament for the treatment of CNSdisorders.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred or narrowedaspects/embodiments of the invention noted herein. Any and allembodiments of the present invention may be taken in conjunction withany other embodiment or embodiments to describe an additionalembodiment. Each individual element of an embodiment is intended to betaken individually as its own independent embodiment. Furthermore, anyelement of an embodiment is meant to be combined with any and all otherelements from any embodiment to describe an additional embodiment.

Definitions

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

Acid functionalities include carboxylic acids, carboxylic acid esters,tetrazole, SO₂OR³, and PO(OR³)₂.

The compounds herein described may have asymmetric centers, geometriccenters (e.g., double bond), or both. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms, by synthesis fromoptically active starting materials, or through use of chiralauxiliaries. Geometric isomers of olefins, C═N double bonds, or othertypes of double bonds may be present in the compounds described herein,and all such stable isomers are included in the present invention.Specifically, cis and trans geometric isomers of the compounds of thepresent invention may also exist and may be isolated as a mixture ofisomers or as separated isomeric forms. All processes used to preparecompounds of the present invention and intermediates made therein areconsidered to be part of the present invention. All tautomers of shownor described compounds are also considered to be part of the presentinvention.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium. Isotopesof carbon include C-13 and C-14.

Examples of the molecular weight of the compounds of the presentinvention include (a) less than about 500, 550, 600, 650, 700, 750, 800,850, 900, 950, or 1000 grams per mole; (b) less than about 950 grams permole; (c) less than about 850 grams per mole; and, (d) less than about750 grams per mole.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

“Alkoxy” represents an alkyl group as defined above with the indicatednumber of hydrocarbon atoms attached through an oxygen bridge. C₁₋₆alkoxy, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Examples ofalkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Counterion” is used to represent a small, negatively charged species,such as chloride, bromide, hydroxide, acetate, and sulfate.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic. Examples of aryl includefluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 memberedmonocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic,and which consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S. If theheteroaryl group is bicyclic or tricyclic, then at least one of the twoor three rings must contain a heteroatom, though both or all three mayeach contain one or more heteroatoms. If the heteroaryl group isbicyclic or tricyclic, then only one of the rings must be aromatic. TheN group may be N, NH, or N-substituent, depending on the chosen ring andif substituents are recited. The nitrogen and sulfur heteroatoms mayoptionally be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heteroarylring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heteroaryl rings describedherein may be substituted on carbon or on a nitrogen atom if theresulting compound is stable.

Examples of heteroaryl includes acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preventing the deposition of adipose tissue covers methods of treatingwherein the levels of adipose tissue of a subject remain about the sameas prior to being treated in accordance with the present invention(i.e., its pre-administration level) or not more than about 1, 2, 3, 4,5, 6, 7, 8, 9, or 10% greater than pre-administration level(particularly when the subject is pre-disposed to increasing adiposetissue levels).

Reversing the deposition of adipose tissue covers methods of treatingwherein the levels of adipose tissue of a subject are lower than thoseprior to being treated in accordance with the present invention (i.e.,its pre-administration level). Examples of lower include 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% or more lowerthan pre-administration level.

Mammal and patient covers warm blooded mammals that are typically undermedical care (e.g., humans and domesticated animals). Examples ofmammals include (a) feline, canine, equine, bovine, and human and (b)human.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, e.g., arresting it development; and/or (c)relieving the disease-state, e.g., causing regression of the diseasestate until a desired endpoint is reached. Treating also includes theamelioration of a symptom of a disease (e.g., lessen the pain ordiscomfort), wherein such amelioration may or may not be directlyaffecting the disease (e.g., cause, transmission, expression, etc.).

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat obesity or another indication listed herein.“Therapeutically effective amount” also includes an amount of thecombination of compounds claimed that is effective to treat the desiredindication. The combination of compounds is preferably a synergisticcombination. Synergy, as described, for example, by Chou and Talalay,Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of thecompounds when administered in combination is greater than the additiveeffect of the compounds when administered alone as a single agent. Ingeneral, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased effect, or some other beneficial effect ofthe combination compared with the individual components.

Utility

Obesity is defined as having a body mass index (BMI) of 30 or above. Theindex is a measure of an individual's body weight relative to height.BMI is calculated by dividing body weight (in kilograms) by height (inmeters) squared. Normal and healthy body weight is defined as having aBMI between 20 and 24.9. Overweight is defined as having a BMI of 25 orabove. Obesity has reached epidemic proportions in the U.S., with 44million obese Americans, and an additional eighty million deemedmedically overweight.

Obesity is a disease characterized as a condition resulting from theexcess accumulation of adipose tissue, especially adipose tissuelocalized in the abdominal area. It is desirable to treat overweight orobese patients by reducing their amount of adipose tissue, and therebyreducing their overall body weight to within the normal range for theirsex and height. In this way, their risk for co-morbidities such asdiabetes and cardiovascular disease will be reduced. It is alsodesirable to prevent normal weight individuals from accumulatingadditional, excess adipose tissue, effectively maintaining their bodyweights at a BMI<25, and preventing the development of co-morbidities.It is also desirable to control obesity, effectively preventingoverweight and obese individuals from accumulating additional, excessadipose tissue, reducing the risk of further exacerbating theirco-morbidities.

There exist two forms of MAO, designated MAO-A and MAO-B. The two formsdiffer with respect to substrate and inhibitor specificities and aminoacid number and sequence. A preferred substrate for MAO-B isbeta-phenylethylamine. In contrast, a preferred substrate for MAO-A isserotonin. Some MAO inhibitors show selectivity for MAO-A or for MAO-B,whereas other MAO inhibitors show little, if any selectivity. Forexample, the MAO inhibitor clorgyline preferentially inhibits MAO-A; theMAO inhibitor L-selegiline preferentially inhibits MAO-B; and, the MAOinhibitor iproniazid is non-selective (i.e., has a similar affinity forboth). Examples of selectivity include a compound having about 2, 3, 4,5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700,800, 900, 1000, or more fold higher affinity for one form of MAO thanfor the other form. One of ordinary skill in the art recognizes thatthere can be some difficulty in classifying MAO inhibitors. Somecompounds may selectively inhibit one form of MAO in vitro and then losetheir selectivity in vivo. Also, selectivity of a compound may vary fromspecies to species or from tissue to tissue. In the context of thepresent invention, it is desirable to inhibit MAO-B activity in vivo ina mammal. Thus, selectivity and affinity are based on the in vivoactivity of the MAO inhibitor and the mammalian species to which it isbeing or to be administered. Examples of the selectivity of a MAO-Binhibitor of the present invention include (a) at least a 2, 3, 4, 5, 6,7, 8, 9, 10, 20, 30, 40, 50, to 100-fold greater affinity for MAO-B thanMAO-A in the mammalian species (e.g., human) to be treated and (b) atleast 100-fold greater affinity for MAO-B than MAO-A in the mammalianspecies (e.g., human) to be treated.

Some of the compounds of the present invention have been designed tohave reduced CNS exposure by virtue of their inability or limitedability to penetrate the blood-brain barrier (e.g., quaternary salts oracid substituents) or by their participation in active transportsystems, thus reducing centrally mediated side-effects, a potentialproblem with many anti-obesity agents.

Other compounds of the present invention are expected to penetrate theblood-brain barrier and therefore also be useful to treat CNS disorders(e.g., Parkinson's disease, depression, and Alzheimer's disease).

MAO enzymes are also located in a number of peripheral (non-CNS)tissues, including adipose tissue, muscle and liver. In order to treatnon-CNS disorders (e.g., obesity, diabetes, and/or cardiometabolicdisorders), it is necessary to administer enough of a drug sufficient toinhibit MAO in peripheral tissues. MAO inhibitors in use today to treatvarious psychiatric and neurological diseases, regardless of route ofadministration, enter the CNS from the systemic circulation. Whilepresent in the systemic circulation, such drugs have access toperipheral tissues, including adipose tissue, liver, and muscle. One ofskill in the art recognizes that MAO inhibitors intended to enter theCNS from the systemic circulation in order to treat psychiatric andneurological diseases also have access to MAO in peripheral tissues,including adipose tissue, liver, and muscle. Thus, an MAO inhibitoruseful for treating non-CNS disorders may have some access to the CNSfrom the systemic circulation.

Drugs enter the CNS from the systemic circulation by crossing theblood-brain barrier (BBB). The BBB is a highly specialized ‘gate-keeper’that protects the brain by preventing the entry of many potentiallyharmful substances into the CNS from the systemic circulation. Much isknown about the BBB, and of the physical-chemical properties requiredfor compounds transported across it.

Drugs that do not cross the BBB into the CNS or that are readilyeliminated through transport mechanisms (J Clin Invest. 97, 2517 (1996))are known in the literature and have low CNS activity due to theirinability to develop brain levels necessary for pharmacological action.The BBB has at least one mechanism to remove drugs prior to theiraccumulation in the CNS. P-Glycoproteins (P-gp) localized in plasmamembrane of the BBB can influence the brain penetration andpharmacological activity of many drugs through translocation acrossmembranes. The lack of accumulation into the brain by some drugs can beexplained by their active removal from the brain by P-gp residing in theBBB. For example, the typical opioid drug loperamide, clinically used asan antidiarrheal, is actively removed from the brain by P-gp, thusexplaining its lack of opiate-like CNS effects. Another example isdomperidone, a dopamine receptor blocker that participates in the P-gptransport (J Clin Invest. 97, 2517 (1996)). Whereas dopamine receptorblockers that cross the BBB can be used to treat schizophrenia, thereadily-eliminated domperidone can be used to prevent emesis, withoutthe likelihood of producing adverse CNS effects.

In addition to the above compounds, agents possessing structuralcharacteristics that retard or prevent BBB penetration or contribute toparticipation in active elimination processes have been identified invarious classes of therapeutics. These include antihistamines (DrugMetab. Dispos. 31, 312 (2003)), beta-adrenergic receptor antagonists(B-blockers)(Eur. J. Clin. Pharmacol. 28, Suppl: 21-3 (1985); Br. J.Clin. Pharmacol., 11 (6), 549-553 (1981)), non-nucleoside reversetranscriptase inhibitors (NNRTIs)(J. Pharm Sci., 88 (10) 950-954(1999)), and opioid antagonists. This latter group has been tested inrelation to their activity in the GI tract. These peripherally selectiveopioid antagonists are described in various US patents as being usefulin the treatment of non-CNS pathologies in mammals, in particular thoseof the GI tract (see U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171;U.S. Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238).

Other types of non-brain penetrant compounds can be prepared through thecreation of a charge within the molecule. Thus, the addition of a methylgroup to the tertiary amine functionality of the drugs scopolamine oratropine, unlike the parent molecules, prevents their passage across theBBB through the presence of a positive charge. However, the newmolecules (methyl-scopolamine and methyl-atropine) retain their fullanticholinergic pharmacological properties. As such, these drugs canalso be used to treat peripheral diseases, without the concern ofadverse CNS effects. The quaternary ammonium compound methylnaltrexoneis also used for the prevention and/or treatment of opioid andnon-opioid induced side effects associated with opioid administration.

MAO-B inhibitors such as selegiline have been useful in the treatment ofCNS disorders. The unexpected discovery that the anti-obesity activitymediated by these agents is mediated by a non-CNS mechanism may make itdesirable that the compounds of the present invention be peripherallyrestricted, i.e., have an inability or limited ability to cross the BBBor be readily eliminated from the brain through active transportsystems, when a non-CNS disorder is to be treated. It may be desirablefor the compounds of the present invention to be peripherallyrestricted, which in turn will result in no or very limited CNS effects.Compounds that provide peripherally mediated anti-obesity propertiesshould result in therapeutic agents with greater safety, as previouslydemonstrated in earlier classes of peripherally restricted agents. Itcan be desirable that the compounds of the present invention, whenadministered in a therapeutically effective amount, have no or verylimited CNS effects. It can also be desirable that the lack of CNSeffects is a result of the compounds of the present invention havingminimal brain concentrations when administered in therapeuticallyeffective amounts. In this context, minimal brain concentrations meanslevels that are too low to be therapeutically effective for thetreatment of a CNS indication or too low to cause significant ormeasurable deleterious or undesired side effects. It is noted that CNSactivity is desirable when seeking to treat a CNS disorder.

Compound A is lazabemide when A¹ is N; A² is C—Cl; A, A³, and A⁴ are allCH; Q is C═O; and R, R¹, and R² are all H. Lazabemide is a drug thatcrosses the BBB and is indicated, but not marketed, for the treatment ofParkinson's disease. In compound A, one of A, A¹, A², A³, A⁴, and Q is agroup capable of reducing or limiting the CNS activity of compound A.This reduced or limited CNS activity occurs via at least one of A, A¹,A², A³, A⁴, and Q being a group that either limits compound A's abilityto cross the BBB relative to that of lazabemide or enables it to beactively removed at a rate greater than that of lazabemide. Examples ofbrain levels of compound A include levels that are (a) from 50, 55, 60,65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100%lower than lazabemide, when administered at the same dosage; (b) from90, 91, 92, 93, 94, 95, 96, 97, 98, 99, to 100% lower than lazabemide,when administered at the same dosage; and, (c) from 98, 99, to 100%lower than lazabemide, when administered at the same dosage.

Most methods of treating obesity are dependent on a significantreduction in energy intake, either by a decrease in food intake (e.g.,sibutramine) or by inhibition of fat absorption (e.g., orlistat). In thepresent invention, it can be desirable for adipose tissue to besignificantly reduced in the absence of a significant reduction in foodintake. The weight loss, as a result of the present invention, comesfrom the treatment with an MAO-B inhibitor, largely independent ofappetite and food intake. Examples of the level of food intake duringadipose tissue loss include (a) food intake is maintained, increased orabout 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20% below the normal range of the subject prior to being treatedin accordance with the present invention (i.e., its pre-administrationlevel); (b) food intake is maintained, increased, or about 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below itspre-administration level; (c) food intake is maintained, increased orabout 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below its pre-administrationlevel; and (d) food intake level is maintained, increased or about 0, 1,2, 3, 4, or 5% below its pre-administration level.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of lean muscle mass. This is particularly evident incancer patients who show a wasting of all body tissue components,including adipose tissue and lean muscle mass. In the present invention,however, it can be desirable for body fat to be significantly reduced inthe absence of a significant reduction in lean body mass. Adipose tissueloss comes from treatment with an MAO-B inhibitor, independent of asignificant change in lean body mass. Examples of the level of lean bodymass during adipose tissue loss include (a) lean body mass ismaintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, or 30% below the normal range of the subject prior to beingtreated in accordance with the present invention (i.e., itspre-administration level); (b) lean body mass is maintained, increased,or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,or 15% below pre-administration levels; (c) lean body mass ismaintained, increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8,9, or 10% below pre-administration levels; and (d) lean body mass ismaintained, increased, or is no more than about 1, 2, 3, 4, or 5% belowpre-administration levels.

In some cases, loss of adipose tissue can be accompanied by aconcomitant loss of water mass. This is particularly evident with dietregimens that promote dehydration. In the present invention, it can bedesirable for body fat to be significantly reduced in the absence of asignificant reduction in water mass. In other words, adipose tissue losscomes from treatment with an MAO-B inhibitor, independent of asignificant change in water mass. Examples of the level of water massduring adipose tissue loss include (a) water mass is maintained,increased, or is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,or 30% below the normal range of the subject prior to being treated inaccordance with the present invention (i.e., its pre-administrationlevel); (b) water mass is maintained, increased, or is no more thanabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% belowpre-administration levels; (c) water mass is maintained, increased, oris no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% belowpre-administration levels; and (d) water mass is maintained, increased,or is no more than about 1, 2, 3, 4, or 5% below pre-administrationlevels.

Sibutramine and orlistat are currently marketed for use in the treatmentof obesity. These two compounds achieve weight loss through entirelydifferent mechanisms. Sibutramine, a CNS appetite suppressant, inhibitsthe neuronal reuptake of serotonin and noradrenaline. Orlistat inhibitsgut lipase enzymes that are responsible for breaking down ingested fat.

The mechanism of action of MAO-B inhibitors is believed to be entirelydifferent from appetite suppressants, gut lipase inhibitors, and otheragents with similar indications (e.g., serotonin agonists, leptin, andfatty acid synthase inhibitors). Co-administration of a MAO-B inhibitortogether with one or more other agents that are useful for treating theindications described above (e.g., obesity, diabetes, cardiometabolicdisorders, and a combination thereof) is expected to be beneficial, byproducing, for example, either additive or synergistic effects. Examplesof additional agents include an appetite suppressant and a lipaseinhibitor. Therefore, the present invention provides a method oftreating obesity, diabetes, and/or cardiometabolic disorders, comprisingadministering a therapeutically effective amount of a compound of thepresent invention and a second component selected from an appetitesuppressant (e.g., sibutramine, phentermine, fenfluramine) and a gutlipase inhibitor (e.g., orlistat).

MAO-B inhibitors are expected to promote weight loss without appreciablyreducing caloric intake. Co-administration of an MAO-B inhibitortogether with an appetite suppressant is expected to produce eitheradditive or synergistic effects on weight loss. Similarly,co-administration of an MAO-B inhibitor together with a lipase inhibitoris expected to produce either additive or synergistic effects on weightloss.

The ability of compounds to inhibit MAOs can be determined using themethod of R. Uebelhack et al., Pharmacopsychiatry 31, 187-192 (1988)(asdescribed below).

Preparation of platelet-rich plasma and platelets. Venous blood fromhealthy subjects was collected between 8 and 8.30 a.m. after anovernight fast into EDTA-containing vacutainer tubes (11.6 mg EDTA/mlblood). After centrifugation of the blood at 250×g for 15 minutes at 20°C., the supernatant platelet-rich plasma (PRP) was collected and thenumber of platelets in PRP counted with a cell counter (MOIAB, Hilden,Germany). 2 ml of PRP was spun at 1500×g for 10 min to yield a plateletpellet. The pellet was washed three times with ice-cold saline,resuspended in 2 ml Soerensen phoshate buffer, pH 7.4 and stored at −18°C. for one day.

MAO assay. Fresh PRP or frozen platelet suspension (100 μL) wasgenerally preincubated for 10 min in the absence or presence of drugs at37° C. in 100 μL of 0.9% NaCl solution or phosphate buffer pH 7.4,respectively, at 37° C. 50 μL of2-phenylethylamine-[ethyl-1-14C]hydrochloride (PEA) solution (specificactivity 56 Ci/mol, Amersham) was then added in a final concentration of5 μM, and the incubation was continued for 30 min. The reaction wasterminated by the addition of 50 μL of 4M HClO₄. The reaction product ofMAO, phenylacetaldehyde, was extracted into 2 mL of n-hexane. An aliquotof the organic phase was added to scintillator cocktail and theradioactivity was determined using a liquid scintillation counter.Product formation was linear with time for at least 60 min withappropriate platelet numbers. Blank values were obtained by including 2mM pargyline in the incubation mixtures. All assays were performed induplicate.

The ability of compounds to inhibit MAO activity can also be determinedusing the following method. cDNA's encoding human MAO-B can betransiently transfected into EBNA cells using the procedure described byE.-J. Schlaeger and K. Christensen (Transient Gene Expression inMammalian Cells Grown in Serum-free Suspension Culture; Cytotechnology,15: 1-13, 1998). After transfection, cells are homogeneized by means ofa Polytron homogeneiser in 20 mM Tris HCl buffer, pH 8.0, containing 0.5mM EGTA and 0.5 mM phenylmethanesulfonyl fluoride. Cell membranes areobtained by centrifugation at 45,000×g and, after two rinsing steps with20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA, membranes areeventually re-suspended in buffer and aliquots stored at −80° C. untiluse.

MAO-B enzymatic activity can be assayed using a spectrophotometric assayadapted from the method described by M. Zhou and N. Panchuk-Voloshina (AOne-Step Fluorometric Method for the Continuous Measurement of MonoamineOxidase Activity, Analytical Biochemistry, 253: 169-174, 1997). Briefly,membrane aliquots are incubated in 0.1 M potassium phosphate buffer, pH7.4, for 30 min at 37° C. with or without various concentrations of thecompounds. After incubation, the enzymatic reaction is started by theaddition of the MAO substrate tyramine together with 1 U/ml horse-radishperoxidase (Roche Biochemicals) and 80 μMN-acetyl-3,7,-dihydroxyphenoxazine (Amplex Red, Molecular Probes). Thesamples are further incubated for 30 min at 37° C. in a final volume of200 μl and absorbance is determined at a wavelength of 570 nm using aSpectraMax plate reader (Molecular Devices). Background (non-specific)absorbance is determined in the presence of 10 μM L-deprenyl for MAO-B.IC₅₀ values are determined from inhibition curves obtained using nineinhibitor concentrations in duplicate, by fitting data to a fourparameter logistic equation.

Compounds of the present invention are expected to be MAO-B inhibitors.Representative compounds have been tested, as measured in the assaydescribed herein, and have been shown to be active as their IC₅₀ valueswere found to be in the range of ≦10 μM. Compounds of the presentinvention are considered to be MAO-B inhibitors if they have an IC₅₀value less than or equal to 10 μM. Additional examples of desirableactivity levels of MAO-B inhibitors useful in the present inventioninclude (a) an IC₅₀ value of 1 μM or lower, (b) an IC₅₀ value of 0.1 μMor lower, (c) an IC₅₀ value of 0.01 μM or lower, (d) an IC₅₀ value of0.001 μM or lower, and (e) an IC₅₀ value of 0.0001 μM or lower.

In the present invention, MAO-B inhibitor(s) can be administeredenterally, parenterally, orally, and transdermally. One skilled in thisart is aware that the routes of administering the compounds of thepresent invention may vary significantly. In addition to other oraladministrations, sustained release compositions may be favored. Otherexamples of routes include injections (e.g., intravenous, intramuscular,and intraperitoneal); subcutaneous; subdermal implants; buccal,sublingual, topical (e.g., a dermal or transdermal patch), rectal,vaginal, and intranasal administrations. Bioerodible, non-bioerodible,biodegradable, and non-biodegradable systems of administration may alsobe used.

If a solid composition in the form of tablets is prepared, the mainactive ingredient can be mixed with a pharmaceutical vehicle, examplesof which include silica, starch, lactose, magnesium stearate, and talc.The tablets can be coated with sucrose or another appropriate substanceor they can be treated so as to have a sustained or delayed activity andso as to release a predetermined amount of active ingredientcontinuously. Gelatin capsules can be obtained by mixing the activeingredient with a diluent and incorporating the resulting mixture intosoft or hard gelatin capsules. A syrup or elixir can contain the activeingredient in conjunction with a sweetener, which is preferablycalorie-free, an antiseptic (e.g., methylparaben and/or propylparaben),a flavoring, and an appropriate color. Water-dispersible powders orgranules can contain the active ingredient mixed with dispersants orwetting agents or with suspending agents such as polyvinylpyrrolidone,as well as with sweeteners or taste correctors. Rectal administrationcan be effected using suppositories, which are prepared with bindersmelting at the rectal temperature (e.g., cocoa butter and/orpolyethylene glycols). Parenteral administration can be effected usingaqueous suspensions, isotonic saline solutions, or injectable sterilesolutions, which contain pharmacologically compatible dispersants and/orwetting agents (e.g., propylene glycol and/or polyethylene glycol). Theactive ingredient can also be formulated as microcapsules ormicrospheres, optionally with one or more carriers or additives. Theactive ingredient can also be presented in the form of a complex with acyclodextrin, for example α-, β-, or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin, and/or methyl-β-cyclodextrin.

The dose of the MAO-B inhibitor administered daily will vary on anindividual basis and to some extent may be determined by the severity ofthe disease being treated (e.g., obesity). The dose of the MAO-Binhibitor will also vary depending on the MAO-B inhibitor administered.An example of a range of dosages of an MAO-B inhibitor is about from0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01,0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1.0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 76, 80, 85, 90, 95, to 100 mg/kg of mammalbody weight. The MAO-B inhibitor can be administered in a single dose orin a number of smaller doses over a period of time. The length of timeduring which the MAO-B inhibitor is administered varies on an individualbasis, and can continue until the desired results are achieved (i.e.,reduction of body fat, or prevention of a gain in body fat). Therapycould, therefore, last from 1 day to weeks, months, or even yearsdepending upon the subject being treated, the desired results, and howquickly the subject responds to treatment in accordance with the presentinvention.

A possible example of a tablet of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 100 Powdered lactose 95 Whitecorn starch 35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10Magnesium stearate 2 Tablet weight 250

A possible example of a capsule of the present invention is as follows.

Ingredient mg/Tablet Active ingredient 50 Crystalline lactose 60Microcrystalline cellulose 34 Talc 5 Magnesium stearate 1 Capsule fillweight 150

In the above capsule, the active ingredient has a suitable particlesize. The crystalline lactose and the microcrystalline cellulose arehomogeneously mixed with one another, sieved, and thereafter the talcand magnesium stearate are admixed. The final mixture is filled intohard gelatin capsules of suitable size.

A possible example of an injection solution of the present invention isas follows.

Ingredient mg/Tablet Active substance 1.0 mg 1 N HCl 20.0 μl acetic acid0.5 mg NaCl 8.0 mg Phenol 10.0 mg 1 N NaOH q.s. ad pH 5 H₂O q.s. ad 1 mLSynthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

As shown in Scheme 1, nitrobenzoic acid can be treated with ethylchloroformate in an appropriate solvent such as methylene chloride inthe presence of triethylamine and the mixed anhydride that should beformed can be reacted with t-butyl (2-aminoethyl)carbamate to afford thebenzamide derivative (step a). The nitrobenzene when treated with sodiumdithionite in aqueous dioxane containing ammonium hydroxide solutionshould yield the aniline derivative (step b). Alkylation of the anilinewith ethyl bromoacetate under basic conditions should give the ester(step c) that can be hydrolyzed with lithium hydroxide in aqueous THF togive the acid (step d). Removal of the t-BOC group using TFA inmethylene chloride should produce the amino acid (step e).Alternatively, the aniline derivative can be sulfonylated withmethanesulfonyl chloride to give the sulfonamide (step f), andsubsequent removal of the t-BOC group using TFA in methylene chlorideshould give the aminoethylbenzamide derivative (step g).

As described in Scheme 2, benzyloxybenzoic acid can be treated withethyl chloroformate in an appropriate solvent such as methylene chloridein the presence of triethylamine and the mixed anhydride that should beformed can be reacted with t-butyl (2-aminoethyl)carbamate to afford thebenzamide derivative (step a). Removal of the benzyl group can beachieved using palladium-catalyzed hydrogenolysis in ethanol to yieldthe phenol (step b). The phenol can be alkylated with ethyl bromoacetateunder basic conditions to give the ester (step c) that can be hydrolyzedwith lithium hydroxide in aqueous THF to give the acid (step d). Removalof the t-BOC group using TFA in methylene chloride should produce theamino acid (step e). Alternatively, the phenol can be alkylated with 1,2dibromoethane to give the alkyl halide (step f). Treatment of the alkylhalide with trimethylamine should give the quaternary ammonium salt(step g) and subsequent removal of the t-BOC group with TFA in methylenechloride solution should afford the aminoethylbenzamide derivative (steph). Removal of the t-BOC group from the product of step a using TFA inmethylene chloride will provide the benzyloxy amino compound (step i).

Alternatively as shown in Scheme 3, a substituted benzyloxyacetic acidcan be treated with ethyl chloroformate in an appropriate solvent suchas methylene chloride in the presence of triethylamine, and the mixedanhydride that should form can be reacted witht-butyl(2-aminoethyl)carbamate to afford the benzamide derivative (stepa). If this benzyloxy-substituent possesses an ester functionality, itcan be hydrolyzed with lithium hydroxide in aqueous THF to give the acid(step b). Removal of the t-BOC group using TFA in methylene chlorideshould produce the amino acid (step c). If this benzyloxy-substituentpossesses a nitrile group it can hydrated using aqueous hydrogenperoxide in DMSO in the presence of a base such as potassium carbonateto give the carboxamido group (step d). Removal of the t-BOC group usingTFA in methylene chloride should produce the amino carboxamides (stepe). A nitrile-substituted benzyloxy compound can also be treated withsodium azide and trioctyl tin chloride in xylene at elevatedtemperatures to give the tetrazole derivative which can be immediatelyreacted with trityl chloride in sodium hydroxide solution to afford thetritylated tetrazole (step f). Removal of the trityl group using aqueoushydrochloric acid in THF at about 20-30° C. can be followed by removalof the t-BOC group using TFA in methylene chloride to produce the aminotetrazole (step g).

As illustrated in Scheme 4, a nitrobenzoic acid can be treated withethyl chloroformate in an appropriate solvent such as methylene chloridein the presence of triethylamine and the mixed anhydride that shouldform can be reacted with t-butyl(2-aminoethyl)carbamate to afford thebenzamide derivative (step a). The nitrobenzene derivative can bereduced with Pd/C in the presence of ammonium formate in methanolsolution to yield the aniline derivative (step b). Reductive aminationof the aniline with a benzaldehyde using sodium triacetoxyborohydrideand acetic acid in dichoroethane at about ambient temperature will givethe benzyl amine derivative (step c) Removal of the t-BOC group usingTFA in methylene chloride should produce the aminoamide (step d).Alternatively, the aniline can be treated with a biphenylbenzaldehydeusing conditions described above to afford the phenylbenzylaminederivative (step e). Removal of the t-BOC group using TFA in methylenechloride should produce the aminoamide (step f). If either the phenyl-or biphenyl-amine contains substituents such as esters or nitriles, oralkylidene or oxaklylidene derivatives thereof, the corresponding acids,carboxamides, or tetrazoles can be prepared as described in Scheme 3above.

Scheme 5 depicts how 4-chloro-2-pyridinecarboxylic acid can be treatedwith ethyl chloroformate in an appropriate solvent such as methylenechloride in the presence of triethylamine and the mixed anhydride thusformed can be reacted with t-butyl (2-aminoethyl)carbamate to afford thechloropyridine derivative (step a). Treatment of the pyridinecarboxamido compound with a peracid should give the pyridine N-oxide(step b), and subsequent removal of the t-BOC group with TFA inmethylene chloride solution should afford the aminoethylbenzamidederivative (step c).

As indicated in Scheme 6, 4-chlorosulfonylbenzoic acid or alkylideneanalogs thereof can be treated with t-butyl(2-aminoethyl)carbamate togive the benzene sulfonamide derivative (step a), and subsequent removalof the t-BOC group with TFA in methylene chloride solution should affordthe aminoethylbenzenesulfonamide derivative (step c).

As noted in Scheme 7, 4-chlorosulfonylbenzoic acid or alkylidene analogsthereof can be treated with an alkylamine or a benzyl amine to give thebenzene sulfonamide derivative (step a). Treatment of this acid withethyl chloroformate in an appropriate solvent such as methylene chloridein the presence of triethylamine and the mixed anhydride thus formed canbe reacted with t-butyl(2-aminoethyl)carbamate to afford the benzamidederivative (step b). Subsequent removal of the t-BOC group with TFA inmethylene chloride solution should afford the aminoethylbenzamidederivative (step c).

Scheme 8 describes how 4-chlorosulfony-3-methoxylbenzoic acid can betreated with phenylalanine ethyl ester in the presence of triethylamineto give the benzene sulfonamide derivative (step a). Treatment of thisacid with ethyl chloroformate in an appropriate solvent such asmethylene chloride in the presence of triethylamine and treatment of themixed anhydride that should be formed witht-butyl(2-aminoethyl)carbamate should afford the benzamide derivative(step b). The ester can be hydrolyzed using lithium hydroxide in aqueousTHF solution (step c), and subsequent removal of the t-BOC group withTFA in methylene chloride solution should afford the aminoethylbenzamidederivative (step d). Alternatively, 4-chlorosulfony-3-methoxylbenzoicacid can be treated with t-butyl(2-aminoethyl)carbamate in the presenceof triethylamine to give the benzene sulfonamide derivative (step e).Formation of the mixed anhydride using ethyl chloroformate in anappropriate solvent such as methylene chloride in the presence oftriethylamine, and treatment of the mixed anhydride thus formed with anamino acid ester such as alanine ethyl ester should produce thebenzoylated amino ester derivative (step f). Hydrolysis of the esterusing lithium hydroxide in aqueous THF solution (step g), and subsequentremoval of the t-BOC group with TFA in methylene chloride solutionshould afford the aminoethylphenylsulfonamide derivative (step h).

As described in Scheme 9,4-chlorosulfonyl-2-ethoxycarbonylmethoxy-benzoic acid can be treatedwith methyl amine in the presence of triethylamine to give the benzenesulfonamide derivative (step a). Treatment of this acid with ethylchloroformate in an appropriate solvent such as methylene chloride inthe presence of triethylamine and exposure of the mixed anhydride thusformed to t-butyl(2-aminoethyl)carbamate should afford the benzamidederivative (step b). The ester can be hydrolyzed using lithium hydroxidein aqueous THF solution (step c), and subsequent removal of the t-BOCgroup with TFA in methylene chloride solution should afford theaminoethylbenzamide derivative (step d).

Scheme 10 shows 6-methylsulfonamidonicotinic acid can be treated withethyl chloroformate in an appropriate solvent such as methylene chloridein the presence of triethylamine and the mixed anhydride thus formed canbe reacted with t-butyl(2-aminoethyl)carbamate to afford the substitutedpyridyl-carboxamido derivative (step a). Subsequent removal of the t-BOCgroup with TFA in methylene chloride solution should afford theaminoethylnicotinamide derivative (step b).

As shown in Scheme 11, 3-methylsulfonamido-2-pyrazine carboxylic acidcan be treated with ethyl chloroformate in an appropriate solvent suchas methylene chloride in the presence of triethylamine and the mixedanhydride thus formed can be reacted with t-butyl(2-aminoethyl)carbamateto afford the substituted pyrazinecarboxamido derivative (step a).Subsequent removal of the t-BOC group with TFA in methylene chloridesolution should afford the aminoethylpyrazinecarboxamide derivative(step b).

Scheme 12 depicts how monoalkylation of ethyl 4-aminobenzoate with ahalo-polyethylene glycol (PEG), optionally substituted with a terminalt-butyldimethylsilyl (TBDMS), alkyl, benzyl or aralkyl group, in DMF inthe presence of potassium carbonate at 60-100 degrees C. with stirringfor 12-24 hours will afford the PEG anilino ester (step a). Hydrolysisof the ester using lithium hydroxide in aqueous DMF will afford the acid(step b). Treatment of the acid with ethyl chloroformate in anappropriate solvent such as methylene chloride in the presence oftriethylamine will produce the mixed anhydride that will react witht-butyl(2-aminoethyl)carbamate to afford the benzamide derivative (stepc). Subsequent removal of the t-BOC group with TFA in methylene chloridesolution should afford the aminoethylbenzamide derivative (step d). Inthe case where R′ is t-butyldimethylsilyl, further treatment withtetrabutylammonium fluoride in THF will give the PEG pendants withterminal hydroxyl groups (step e). The various PEG-halides can beprepared by procedures described in Nuclear Medicine and Biology, 32,799 (2005), or are commercially available.

As illustrated in Scheme 13, alkylation of ethyl 5-hydroxypicolinatewith a halo-polyethylene glycol (PEG), optionally substituted with aterminal t-butyldimethylsilyl (TBDMS), alkyl, benzyl or aralkyl group,in DMF in the presence of potassium carbonate at 60-100 degrees C. withstirring for 12-24 hours will afford the PEG-ether picolinate ester(step a). Hydrolysis of the ester using lithium hydroxide in aqueous DMFwill afford the acid (step b). Treatment of the acid with ethylchloroformate in an appropriate solvent such as methylene chloride inthe presence of triethylamine will produce the mixed anhydride that willreact with t-butyl(2-aminoethyl)carbamate to afford the benzamidederivative (step c). Subsequent removal of the t-BOC group with TFA inmethylene chloride solution should afford the aminoethylbenzamidederivative (step d). In the case where R′ is t-butyldimethylsilyl,further treatment with tetrabutylammonium fluoride in THF will give thePEG pendants with terminal hydroxyl groups (step e). The variousPEG-halides can be prepared by procedures described in Nuclear Medicineand Biology, 32, 799 (2005), or are commercially available.

One stereoisomer of a compound of the present invention may be a morepotent MAO-B inhibitor than its counterpart(s). Thus, stereoisomers areincluded in the present invention. Some of these stereoisomers are shownbelow in Scheme 14. When required, separation of the racemic materialcan be achieved by HPLC using a chiral column or by a resolution using aresolving agent such as described in Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions 1972, 308 or using enantiomerically pureacids and bases. A chiral compound of the present invention may also bedirectly synthesized using a chiral catalyst or a chiral ligand, e.g.,Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio-and diastereo-selective reactions and reagents known to one skilled inthe art of asymmetric synthesis.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Tables I-XIV show representative examples of the compounds of thepresent invention. Each example in each table represents an individualspecies of the present invention.

TABLE I

Ex. # X Y A A¹ A³ 1 CO₂Et H CH CH CH 2 CO₂H H CH CH CH 3 SO₃Et H CH CHCH 4 SO₃H H CH CH CH 5 PO(OEt)₂ H CH CH CH 6 PO(OH)₂ H CH CH CH 7NHCH₂CO₂Et H CH CH CH 8 NHCH₂CO₂H H CH CH CH 9 OCH₂CO₂Et H CH CH CH 10OCH₂CO₂H H CH CH CH 11 NHCH₂CH₂CO₂Et H CH CH CH 12 NHCH₂CH₂CO₂H H CH CHCH 13 OCH₂CH₂CO₂Et H CH CH CH 14 OCH₂CH₂CO₂H H CH CH CH 15NHCH₂CH═CHCO₂Et H CH CH CH 16 NHCH₂CH═CHCO₂H H CH CH CH 17OCH₂CH═CHCO₂Et H CH CH CH 18 OCH₂CH═CHCO₂H H CH CH CH 19 OCH₂CH₂PO(OEt)₂H CH CH CH 20 OCH₂CH₂PO(OH)₂ H CH CH CH 21 OCH₂CH₂N(CH₃)₂ H CH CH CH 22OCH₂CH₂N⁺(CH₃)₃ Cl⁻ H CH CH CH 23 SO₂NHEt H CH CH CH 24 CONHCH(CH₃)CO₂EtH CH CH CH 25 CONHCH(CH₃)CO₂H H CH CH CH 26 CONHCH(CH₂C₆H₅)CO₂Et H CH CHCH 27 CONHCH(CH₂C₆H₅)CO₂H H CH CH CH 28 NHCH₂CONH₂ H CH CH CH 29NHCH₂CH₂CONH₂ H CH CH CH 30 OCH₂CONH₂ H CH CH CH 31 OCH₂CH₂CONH₂ H CH CHCH 32 OCH₂CH₂-tetrazole H CH CH CH

TABLE II

Ex. # X Y A A¹ A³ 1 CO₂Et OCH₃ CH CH CH 2 CO₂H OCH₃ CH CH CH 3 SO₃EtOCH₃ CH CH CH 4 SO₃H OCH₃ CH CH CH 5 PO(OEt)₂ OCH₃ CH CH CH 6 PO(OH)₂OCH₃ CH CH CH 7 NHCH₂CO₂Et OCH₃ CH CH CH 8 NHCH₂CO₂H OCH₃ CH CH CH 9OCH₂CO₂Et OCH₃ CH CH CH 10 OCH₂CO₂H OCH₃ CH CH CH 11 NHCH₂CH₂CO₂Et OCH₃CH CH CH 12 NHCH₂CH₂CO₂H OCH₃ CH CH CH 13 OCH₂CH₂CO₂Et OCH₃ CH CH CH 14OCH₂CH₂CO₂H OCH₃ CH CH CH 15 NHCH₂CH═CHCO₂Et OCH₃ CH CH CH 16NHCH₂CH═CHCO₂H OCH₃ CH CH CH 17 OCH₂CH═CHCO₂Et OCH₃ CH CH CH 18OCH₂CH═CHCO₂H OCH₃ CH CH CH 19 OCH₂CH₂PO(OEt)₂ OCH₃ CH CH CH 20OCH₂CH₂PO(OH)₂ OCH₃ CH CH CH 21 OCH₂CH₂N(CH₃)₂ OCH₃ CH CH CH 22OCH₂CH₂N^(−(CH) ₃)₃ Cl⁻ OCH₃ CH CH CH 23 SO₂NHEt OCH₃ CH CH CH 24CONHCH(CH₃)CO₂Et OCH₃ CH CH CH 25 CONHCH(CH₃)CO₂H OCH₃ CH CH CH 26CONHCH(CH₂C₆H₅)CO₂Et OCH₃ CH CH CH 27 CONHCH(CH₂C₆H₅)CO₂H OCH₃ CH CH CH28 NHCH₂CONH₂ OCH₃ CH CH CH 29 NHCH₂CH₂CONH₂ OCH₃ CH CH CH 30 OCH₂CONH₂OCH₃ CH CH CH 31 OCH₂CH₂CONH₂ OCH₃ CH CH CH 32 OCH₂CH₂-tetrazole OCH₃ CHCH CH 34 OCH₂C₆H₅ OCH₃ CH CH CH 35 OCH₂C₆H₄—Cl(3) OCH₃ CH CH CH 36OCH₂C₆H₄—Cl(4) OCH₃ CH CH CH 37 OCH₂C₆H₄—F(3) OCH₃ CH CH CH 38OCH₂C₆H₄—F(4) OCH₃ CH CH CH 39 OCH₂C₆H₄—CF₃(3) OCH₃ CH CH CH 40OCH₂C₆H₄—CF₃(4) OCH₃ CH CH CH 41 OCH₂C₆H₄—NO₂(3) OCH₃ CH CH CH 42OCH₂C₆H₄—NO₂(4) OCH₃ CH CH CH 43 OCH₂C₆H₄—CH₃(3) OCH₃ CH CH CH 44OCH₂C₆H₄—CH₃(4) OCH₃ CH CH CH 45 OCH₂C₆H₄—OCH₃(3) OCH₃ CH CH CH 46OCH₂C₆H₄—OCH₃(4) OCH₃ CH CH CH 47 OCH₂C₆H₄—NHSO₂CH₃(3) OCH₃ CH CH CH 48OCH₂C₆H₄—NHSO₂CH₃(4) OCH₃ CH CH CH 49 OCH₂C₆H₄—CN(3) OCH₃ CH CH CH 50OCH₂C₆H₄—CN(4) OCH₃ CH CH CH 51 OCH₂C₆H₄—CONH₂(3) OCH₃ CH CH CH 52OCH₂C₆H₄—CONH₂(4) OCH₃ CH CH CH 53 OCH₂C₆H₄—OCH₂CN(3) OCH₃ CH CH CH 54OCH₂C₆H₄—OCH₂CN(4) OCH₃ CH CH CH 55 OCH₂C₆H₄— OCH₃ CH CH CH OCH₂CONH₂(3)56 OCH₂C₆H₄—OCH₂CONH₂ OCH₃ CH CH CH (4) 57 OCH₂C₆H₄CH₂CN(3) OCH₃ CH CHCH 58 OCH₂C₆H₄CH₂CN(4) OCH₃ CH CH CH 59 OCH₂C₆H₄CH₂CONH₂(3) OCH₃ CH CHCH 60 OCH₂C₆H₄CH₂CONH₂(4) OCH₃ CH CH CH 61 OCH₂C₆H₃(CN)₂(3,5) OCH₃ CH CHCH 62 OCH₂C₆H₃(CN)₂(3,5) OCH₃ CH CH CH 63 OCH₂C₆H₃(CONH₂)₂(3,5) OCH₃ CHCH CH 64 OCH₂C₆H₃(CONH₂)₂(3,5) OCH₃ CH CH CH 65 OCH₂C₆H₄C₆H₄CN(2, 3, orOCH₃ CH CH CH 4) 66 OCH₂C₆H₄C₆H₄CONH₂(2, OCH₃ CH CH CH 3, or 4)

TABLE III

Ex. # X Y A A¹ A³ 1. SO₂NHEt OCH₂CO₂Et CH CH CH 2. NHCH₂CONH₂ OCH₂CO₂EtCH CH CH 3. SO₂NHCH₂C₆H₅ OCH₂CO₂Et CH CH CH 4. SO₂NHC₆H₅ OCH₂CO₂Et CH CHCH 5. SO₂NHEt OCH₂CO₂H CH CH CH 6. NHCH₂CONH₂ OCH₂CO₂H CH CH CH 7.SO₂NHCH₂C₆H₅ OCH₂CO₂H CH CH CH 8. SO₂NHC₆H₅ OCH₂CO₂H CH CH CH 9. HOCH₂CO₂Et CH CH CH 10. H OCH₂CO₂H CH CH CH

TABLE IV

Ex. # X Y A A¹ A³ 1 CO₂Et H N CH CH 2 CO₂H H N CH CH 3 SO₃Et H N CH CH 4SO₃H H N CH CH 5 PO(OEt)₂ H N CH CH 6 PO(OH)₂ H N CH CH 7 NHCH₂CO₂Et H NCH CH 8 NHCH₂CO₂H H N CH CH 9 OCH₂CO₂Et H N CH CH 10 OCH₂CO₂H H N CH CH11 NHCH₂CH₂CO₂Et H N CH CH 12 NHCH₂CH₂CO₂H H N CH CH 13 OCH₂CH₂CO₂Et H NCH CH 14 OCH₂CH₂CO₂H H N CH CH 15 NHCH₂CH═CHCO₂Et H N CH CH 16NHCH₂CH═CHCO₂H H N CH CH 17 OCH₂CH═CHCO₂Et H N CH CH 18 OCH₂CH═CHCO₂H HN CH CH 19 OCH₂CH₂PO(OEt)₂ H N CH CH 20 OCH₂CH₂PO(OH)₂ H N CH CH 21OCH₂CH₂N(CH₃)₂ H N CH CH 22 OCH₂CH₂N⁺(CH₃)₃ Cl⁻ H N CH CH 23 SO₂NHEt H NCH CH 24 CONHCH(CH₃)CO₂Et H N CH CH 25 CONHCH(CH₃)CO₂H H N CH CH 26CONHCH(CH₂C₆H₅)CO₂Et H N CH CH 27 CONHCH(CH₂C₆H₅)CO₂H H N CH CH 28NHCH₂CONH₂ H N CH CH 29 NHCH₂CH₂CONH₂ H N CH CH 30 OCH₂CONH₂ H N CH CH31 OCH₂CH₂CONH₂ H N CH CH 32 OCH₂CH₂-tetrazole H N CH CH

TABLE V

Ex. # X Y A A¹ A³ 1 CO₂Et H CH N CH 2 CO₂H H CH N CH 3 SO₃Et H CH N CH 4SO₃H H CH N CH 5 PO(OEt)₂ H CH N CH 6 PO(OH)₂ H CH N CH 7 NHCH₂CO₂Et HCH N CH 8 NHCH₂CO₂H H CH N CH 9 OCH₂CO₂Et H CH N CH 10 OCH₂CO₂H H CH NCH 11 NHCH₂CH₂CO₂Et H CH N CH 12 NHCH₂CH₂CO₂H H CH N CH 13 OCH₂CH₂CO₂EtH CH N CH 14 OCH₂CH₂CO₂H H CH N CH 15 NHCH₂CH═CHCO₂Et H CH N CH 16NHCH₂CH═CHCO₂H H CH N CH 17 OCH₂CH═CHCO₂Et H CH N CH 18 OCH₂CH═CHCO₂H HCH N CH 19 OCH₂CH₂PO(OEt)₂ H CH N CH 20 OCH₂CH₂PO(OH)₂ H CH N CH 21OCH₂CH₂N(CH₃)₂ H CH N CH 22 OCH₂CH₂N⁺(CH₃)₃ Cl⁻ H CH N CH 23 SO₂NHEt HCH N CH 24 CONHCH(CH₃)CO₂Et H CH N CH 25 CONHCH(CH₃)CO₂H H CH N CH 26CONHCH(CH₂C₆H₅)CO₂Et H CH N CH 27 CONHCH(CH₂C₆H₅)CO₂H H CH N CH 28NHCH₂CONH₂ H CH N CH 29 NHCH₂CH₂CONH₂ H CH N CH 30 OCH₂CONH₂ H CH N CH31 OCH₂CH₂CONH₂ H CH N CH 32 OCH₂CH₂-tetrazole H CH N CH 33 OCH₂CH₂C₆H₅H CH N CH 34 OCH₂C₆H₅ H CH N CH 35 OCH₂C₆H₄—Cl(3) H CH N CH 36OCH₂C₆H₄—Cl(4) H CH N CH 37 OCH₂C₆H₄—F(3) H CH N CH 38 OCH₂C₆H₄—F(4) HCH N CH 39 OCH₂C₆H₄—CF₃(3) H CH N CH 40 OCH₂C₆H₄—CF₃(4) H CH N CH 41OCH₂C₆H₄—NO₂(3) H CH N CH 42 OCH₂C₆H₄—NO₂(4) H CH N CH 43OCH₂C₆H₄—CH₃(3) H CH N CH 44 OCH₂C₆H₄—CH₃(4) H CH N CH 45OCH₂C₆H₄—OCH₃(3) H CH N CH 46 OCH₂C₆H₄—OCH₃(4) H CH N CH 47OCH₂C₆H₄—NHSO₂CH₃(3) H CH N CH 48 OCH₂C₆H₄—NHSO₂CH₃(4) H CH N CH 49OCH₂C₆H₄—CN(3) H CH N CH 50 OCH₂C₆H₄—CN(4) H CH N CH 51OCH₂C₆H₄—CONH₂(3) H CH N CH 52 OCH₂C₆H₄—CONH₂(4) H CH N CH 53OCH₂C₆H₄—OCH₂CN(3) H CH N CH 54 OCH₂C₆H₄—OCH₂CN(4) H CH N CH 55OCH₂C₆H₄— H CH N CH OCH₂CONH₂(3) 56 OCH₂C₆H₄—OCH₂CONH₂ H CH N CH (4) 57OCH₂C₆H₄CH₂CN(3) H CH N CH 58 OCH₂C₆H₄CH₂CN(4) H CH N CH 59OCH₂C₆H₄CH₂CONH₂(3) H CH N CH 60 OCH₂C₆H₄CH₂CONH₂(4) H CH N CH 61OCH₂C₆H₃(CN)₂(3,5) H CH N CH 62 OCH₂C₆H₃(CN)₂(3,5) H CH N CH 63OCH₂C₆H₃(CONH₂)₂(3,5) H CH N CH 64 OCH₂C₆H₃(CONH₂)₂(3,5) H CH N CH 65OCH₂C₆H₄C₆H₄CN(2, 3, or H CH N CH 4) 66 OCH₂C₆H₄C₆H₄CONH₂(2, H CH N CH3, or 4)

TABLE VI

Ex. # X Y A A¹ A³ 1 CO₂Et H N CH N 2 CO₂H H N CH N 3 SO₃Et H N CH N 4SO₃H H N CH N 5 PO(OEt)₂ H N CH N 6 PO(OH)₂ H N CH N 7 NHCH₂CO₂Et H N CHN 8 NHCH₂CO₂H H N CH N 9 OCH₂CO₂Et H N CH N 10 OCH₂CO₂H H N CH N 11NHCH₂CH₂CO₂Et H N CH N 12 NHCH₂CH₂CO₂H H N CH N 13 OCH₂CH₂CO₂Et H N CH N14 OCH₂CH₂CO₂H H N CH N 15 NHCH₂CH═CHCO₂Et H N CH N 16 NHCH₂CH═CHCO₂H HN CH N 17 OCH₂CH═CHCO₂Et H N CH N 18 OCH₂CH═CHCO₂H H N CH N 19OCH₂CH₂PO(OEt)₂ H N CH N 20 OCH₂CH₂PO(OH)₂ H N CH N 21 OCH₂CH₂N(CH₃)₂ HN CH N 22 OCH₂CH₂N⁺(CH₃)₃ Cl⁻ H N CH N 23 SO₂NHEt H N CH N 24CONHCH(CH₃)CO₂Et H N CH N 25 CONHCH(CH₃)CO₂H H N CH N 26CONHCH(CH₂C₆H₅)CO₂Et H N CH N 27 CONHCH(CH₂C₆H₅)CO₂H H N CH N 28NHCH₂CONH₂ H N CH N 29 NHCH₂CH₂CONH₂ H N CH N 30 OCH₂CONH₂ H N CH N 31OCH₂CH₂CONH₂ H N CH N 32 OCH₂CH₂-tetrazole H N CH N

TABLE VII

Ex. # X Y A A¹ A³ 1 H CO₂Et N CH N 2 H CO₂H N CH N 3 H SO₃Et N CH N 4 HSO₃H N CH N 5 H PO(OEt)₂ N CH N 6 H PO(OH)₂ N CH N 7 H NHCH₂CO₂Et N CH N8 H NHCH₂CO₂H N CH N 9 H OCH₂CO₂Et N CH N 10 H OCH₂CO₂H N CH N 11 HNHCH₂CH₂CO₂Et N CH N 12 H NHCH₂CH₂CO₂H N CH N 13 H OCH₂CH₂CO₂Et N CH N14 H OCH₂CH₂CO₂H N CH N 15 H NHCH₂CH═CHCO₂Et N CH N 16 H NHCH₂CH═CHCO₂HN CH N 17 H OCH₂CH═CHCO₂Et N CH N 18 H OCH₂CH═CHCO₂H N CH N 19 HOCH₂CH₂PO(OEt)₂ N CH N 20 H OCH₂CH₂PO(OH)₂ N CH N 21 H OCH₂CH₂N(CH₃)₂ NCH N 22 H OCH₂CH₂N⁺(CH₃)₃ Cl⁻ N CH N 23 H SO₂NHEt N CH N 24 HCONHCH(CH₃)CO₂Et N CH N 25 H CONHCH(CH₃)CO₂H N CH N 26 HCONHCH(CH₂C₆H₅)CO₂Et N CH N 27 H CONHCH(CH₂C₆H₅)CO₂H N CH N 28 HNHCH₂CONH₂ N CH N 29 H NHCH₂CH₂CONH₂ N CH N 30 H OCH₂CONH₂ N CH N 31 HOCH₂CH₂CONH₂ N CH N 32 H OCH₂CH₂-tetrazole N CH N

TABLE VIII

Ex. # X A 1 CO₂Et CH 2 CO₂H CH 3 OCH₂CH═CHCO₂Et CH 4 OCH₂CH═CHCO₂H CH 5NHCH₂CO₂Et CH 6 NHCH₂CO₂H CH 7 OCH₂CO₂Et CH 8 OCH₂CO₂H CH 9NHCH₂CH₂CO₂Et CH 10 NHCH₂CH₂CO₂H CH 11 OCH₂CH₂CO₂Et CH 12 OCH₂CH₂CO₂H CH13 NHCH₂CH═CHCO₂Et CH 14 NHCH₂CH═CHCO₂H CH 15 OCH₂CH═CHCO₂Et CH 16OCH₂CH═CHCO₂H CH 17 OCH₂CH₂PO(OEt)₂ CH 18 OCH₂CH₂PO(OH)₂ CH 19OCH₂CH₂N(CH₃)₂ CH 20 OCH₂CH₂N⁺(CH₃)₃ Cl⁻ CH 21 CONHCH(CH₃)CO₂Et CH 22CONHCH(CH₃)CO₂H CH 23 CONHCH(CH₂C₆H₅)CO₂Et CH 24 CONHCH(CH₂C₆H₅)CO₂H CH25 NHCH₂CONH₂ CH 26 NHCH₂CH₂CONH₂ CH 27 OCH₂CONH₂ CH 28 OCH₂CH₂CONH₂ CH29 OCH₂CH₂-tetrazole CH 30 OCH₂CH₂C₆H₅ CH 31 OCH₂C₆H₅ CH 32OCH₂C₆H₄—Cl(3) CH 33 OCH₂C₆H₄—Cl(4) CH 34 OCH₂C₆H₄—F(3) CH 35OCH₂C₆H₄—F(4) CH 36 OCH₂C₆H₄—CF₃(3) CH 37 OCH₂C₆H₄—CF₃(4) CH 38OCH₂C₆H₄—NO₂(3) CH 39 OCH₂C₆H₄—NO₂(4) CH 40 OCH₂C₆H₄—CH₃(3) CH 41OCH₂C₆H₄—CH₃(4) CH 42 OCH₂C₆H₄—OCH₃(3) CH 43 OCH₂C₆H₄—OCH₃(4) CH 44OCH₂C₆H₄—NHSO₂CH₃(3) CH 45 OCH₂C₆H₄—NHSO₂CH₃(4) CH 46 OCH₂C₆H₄—CN(3) CH47 OCH₂C₆H₄—CN(4) CH 48 OCH₂C₆H₄—CONH₂(3) CH 49 OCH₂C₆H₄—CONH₂(4) CH 50OCH₂C₆H₄—OCH₂CN(3) CH 51 OCH₂C₆H₄—OCH₂CN(4) CH 52 OCH₂C₆H₄—OCH₂CONH₂(3)CH 53 OCH₂C₆H₄—OCH₂CONH₂(4) CH 54 OCH₂C₆H₄CH₂CN(3) CH 55OCH₂C₆H₄CH₂CN(4) CH 56 OCH₂C₆H₄CH₂CONH₂(3) CH 57 OCH₂C₆H₄CH₂CONH₂(4) CH58 OCH₂C₆H₃(CN)₂(3,5) CH 59 OCH₂C₆H₃(CN)₂(3,5) CH 60OCH₂C₆H₃(CONH₂)₂(3,5) CH 61 OCH₂C₆H₃(CONH₂)₂(3,5) CH 62OCH₂C₆H₄C₆H₄CN(2, 3, or 4) CH 63 OCH₂C₆H₄C₆H₄CONH₂(2, 3, or 4) CH

TABLE IX

Ex. # X A 1 NHCH₂CO₂Et N 2 NHCH₂CO₂H N 3 OCH₂CO₂Et N 4 OCH₂CO₂H N 5NHCH₂CH₂CO₂Et N 6 NHCH₂CH₂CO₂H N 7 OCH₂CH₂CO₂Et N 8 OCH₂CH₂CO₂H N 9NHCH₂CH═CHCO₂Et N 10 NHCH₂CH═CHCO₂H N 11 OCH₂CH═CHCO₂Et N 12OCH₂CH═CHCO₂H N 13 NHCH₂CONH₂ N 14 NHCH₂CH₂CONH₂ N 15 OCH₂CONH₂ N 16OCH₂CH₂CONH₂ N 17 OCH₂CH₂PO(OEt)₂ N 18 OCH₂CH₂PO(OH)₂ N 19OCH₂CH₂N(CH₃)₂ N 20 OCH₂CH₂N⁻(CH₃)₃ Cl⁻ N 21 CONHCH(CH₃)CO₂Et N 22CONHCH(CH₃)CO₂H N 23 CONHCH(CH₂C₆H₅)CO₂Et N 24 CONHCH(CH₂C₆H₅)CO₂H N 25NHCH₂CONH₂ N 26 NHCH₂CH₂CONH₂ N 27 OCH₂CONH₂ N 28 OCH₂CH₂CONH₂ N 29OCH₂CH₂-tetrazole N 30 OCH₂CH₂C₆H₅ N 31 OCH₂C₆H₅ N 32 OCH₂C₆H₄—Cl(3) N33 OCH₂C₆H₄—Cl(4) N 34 OCH₂C₆H₄—F(3) N 35 OCH₂C₆H₄—F(4) N 36OCH₂C₆H₄—CF₃(3) N 37 OCH₂C₆H₄—CF₃(4) N 38 OCH₂C₆H₄—NO₂(3) N 39OCH₂C₆H₄—NO₂(4) N 40 OCH₂C₆H₄—CH₃(3) N 41 OCH₂C₆H₄—CH₃(4) N 42OCH₂C₆H₄—OCH₃(3) N 43 OCH₂C₆H₄—OCH₃(4) N 44 OCH₂C₆H₄—NHSO₂CH₃(3) N 45OCH₂C₆H₄—NHSO₂CH₃(4) N 46 OCH₂C₆H₄—CN(3) N 47 OCH₂C₆H₄—CN(4) N 48OCH₂C₆H₄—CONH₂(3) N 49 OCH₂C₆H₄—CONH₂(4) N 50 OCH₂C₆H₄—OCH₂CN(3) N 51OCH₂C₆H₄—OCH₂CN(4) N 52 OCH₂C₆H₄—OCH₂CONH₂(3) N 53 OCH₂C₆H₄—OCH₂CONH₂(4)N 54 OCH₂C₆H₄CH₂CN(3) N 55 OCH₂C₆H₄CH₂CN(4) N 56 OCH₂C₆H₄CH₂CONH₂(3) N57 OCH₂C₆H₄CH₂CONH₂(4) N 58 OCH₂C₆H₃(CN)₂(3,5) N 59 OCH₂C₆H₃(CN)₂(3,5) N60 OCH₂C₆H₃(CONH₂)₂(3,5) N 61 OCH₂C₆H₃(CONH₂)₂(3,5) N 62OCH₂C₆H₄C₆H₄CN(2, 3, or 4) N 63 OCH₂C₆H₄C₆H₄CONH₂(2, 3, or 4) N

TABLE X

Ex. # X A 1 OCH₂CH₂C₆H₅ CH 2 OCH₂C₆H₅ CH 3 OCH₂C₆H₄—Cl(3) CH 4OCH₂C₆H₄—Cl(4) CH 5 OCH₂C₆H₄—F(3) CH 6 OCH₂C₆H₄—F(4) CH 7OCH₂C₆H₄—CF₃(3) CH 8 OCH₂C₆H₄—CF₃(4) CH 9 OCH₂C₆H₄—NO₂(3) CH 10OCH₂C₆H₄—NO₂(4) CH 11 OCH₂C₆H₄—OCH₃(3) CH 12 OCH₂C₆H₄—OCH₃(4) CH 13OCH₂C₆H₄—NHSO₂CH₃(3) CH 14 OCH₂C₆H₄—NHSO₂CH₃(4) CH 15 OCH₂C₆H₄—CN(3) CH16 OCH₂C₆H₄—CN(4) CH 17 OCH₂C₆H₄—CONH₂(3) CH 18 OCH₂C₆H₄—CONH₂(4) CH 19OCH₂C₆H₄—OCH₂CN(3) CH 20 OCH₂C₆H₄—OCH₂CN(4) CH 21 OCH₂C₆H₄—OCH₂CONH₂(3)CH 22 OCH₂C₆H₄—OCH₂CONH₂(4) CH 23 OCH₂C₆H₄CH₂CN(3) CH 24OCH₂C₆H₄CH₂CN(4) CH 25 OCH₂C₆H₄CH₂CONH₂(3) CH 26 OCH₂C₆H₄CH₂CONH₂(4) CH27 OCH₂C₆H₅CO₂Et(3) CH 28 OCH₂C₆H₅CO₂H(3) CH 29 OCH₂C₆H₅CO₂Et(4) CH 30OCH₂C₆H₅CO₂H(4) CH 31 OCH₂C₆H₅CH₂CO₂Et(3) CH 32 OCH₂C₆H₅CH₂CO₂H(3) CH 33OCH₂C₆H₅CH₂CO₂Et(4) CH 34 OCH₂C₆H₅CH₂CO₂H(4) CH 35 OCH₂C₆H₅OCH₂CO₂Et(3)CH 36 OCH₂C₆H₅OCH₂CO₂H(3) CH 37 OCH₂C₆H₅OCH₂CO₂Et(4) CH 38OCH₂C₆H₅OCH₂CO₂H(4) CH 39 OCH₂C₆H₃(CN)₂(3,5) CH 40 OCH₂C₆H₃(CN)₂(3,5) CH41 OCH₂C₆H₃(CONH₂)₂(3,5) CH 42 OCH₂C₆H₃(CONH₂)₂(3,5) CH 43OCH₂C₆H₄C₆H₄CN(2, 3, or 4) CH 44 OCH₂C₆H₄C₆H₄CONH₂(2, 3, or 4) CH 45OCH₂C₆H₄C₆H₄CO₂Et(2, 3, or 4) CH 46 OCH₂C₆H₄C₆H₄CO₂H(2, 3, or 4) CH 47OCH₂C₆H₄—CH₃(3) CH 48 OCH₂C₆H₄—CH₃(4) CH

TABLE XI

Ex. # X A 1 OCH₂CH₂C₆H₅ N 2 OCH₂C₆H₅ N 3 OCH₂C₆H₄—Cl(3) N 4OCH₂C₆H₄—Cl(4) N 5 OCH₂C₆H₄—F(3) N 6 OCH₂C₆H₄—F(4) N 7 OCH₂C₆H₄—CF₃(3) N8 OCH₂C₆H₄—CF₃(4) N 9 OCH₂C₆H₄—NO₂(3) N 10 OCH₂C₆H₄—NO₂(4) N 11OCH₂C₆H₄—NHSO₂CH₃(3) N 12 OCH₂C₆H₄—NHSO₂CH₃(4) N 13 OCH₂C₆H₄—CN(3) N 14OCH₂C₆H₄—CN(4) N 15 OCH₂C₆H₄—CONH₂(3) N 16 OCH₂C₆H₄—CONH₂(4) N 17OCH₂C₆H₄—OCH₂CN(3) N 18 OCH₂C₆H₄—OCH₂CN(4) N 19 OCH₂C₆H₄—OCH₂CONH₂(3) N20 OCH₂C₆H₄—OCH₂CONH₂(4) N 21 OCH₂C₆H₄CH₂CN(3) N 22 OCH₂C₆H₄CH₂CN(4) N23 OCH₂C₆H₄CH₂CONH₂(3) N 24 OCH₂C₆H₄CH₂CONH₂(4) N 25 OCH₂C₆H₅CO₂Et(3) N26 OCH₂C₆H₅CO₂H(3) N 27 OCH₂C₆H₅CO₂Et(4) N 28 OCH₂C₆H₅CO₂H(4) N 29OCH₂C₆H₅CH₂CO₂Et(3) N 30 OCH₂C₆H₅CH₂CO₂H(3) N 31 OCH₂C₆H₅CH₂CO₂Et(4) N32 OCH₂C₆H₅CH₂CO₂H(4) N 33 OCH₂C₆H₅OCH₂CO₂Et(3) N 34 OCH₂C₆H₅OCH₂CO₂H(3)N 35 OCH₂C₆H₅OCH₂CO₂Et(4) N 36 OCH₂C₆H₅OCH₂CO₂H(4) N 37OCH₂C₆H₃(CN)₂(3,5) N 38 OCH₂C₆H₃(CN)₂(3,5) N 39 OCH₂C₆H₃(CONH₂)₂(3,5) N40 OCH₂C₆H₃(CONH₂)₂(3,5) N 41 OCH₂C₆H₄—OCH₃(3) N 42 OCH₂C₆H₄—OCH₃(4) N43 OCH₂C₆H₄C₆H₄CN(2,3, or 4) N 44 OCH₂C₆H₄C₆H₄CONH₂(2,3, or 4) N 45OCH₂C₆H₄C₆H₄CO₂Et(2,3, or 4) N 46 OCH₂C₆H₄C₆H₄CO₂H(2,3, or 4) N 47OCH₂C₆H₄—CH₃(3) N 48 OCH₂C₆H₄—CH₃(4) N

TABLE XII

Ex. # X A 1 NHCH₂CH₂C₆H₅ CH 2 NHCH₂C₆H₅ CH 3 NHCH₂C₆H₄—Cl(3) CH 4NHCH₂C₆H₄—Cl(4) CH 5 NHCH₂C₆H₄—F(3) CH 6 NHCH₂C₆H₄—F(4) CH 7NHCH₂C₆H₄—CF₃(3) CH 8 NHCH₂C₆H₄—CF₃(4) CH 9 NHCH₂C₆H₄—NO₂(3) CH 10NHCH₂C₆H₄—NO₂(4) CH 11 NHCH₂C₆H₄—NHSO₂CH₃(3) CH 12 NHCH₂C₆H₄—NHSO₂CH₃(4)CH 13 NHCH₂C₆H₄—CN(3) CH 14 NHCH₂C₆H₄—CN(4) CH 15 NHCH₂C₆H₄—CONH₂(3) CH16 NHCH₂C₆H₄—CONH₂(4) CH 17 NHCH₂C₆H₄—OCH₂CN(3) CH 18NHCH₂C₆H₄—OCH₂CN(4) CH 19 NHCH₂C₆H₄—OCH₂CONH₂(3) CH 20NHCH₂C₆H₄—OCH₂CONH₂(4) CH 21 NHCH₂C₆H₄CH₂CN(3) CH 22 NHCH₂C₆H₄CH₂CN(4)CH 23 NHCH₂C₆H₄CH₂CONH₂(3) CH 24 NHCH₂C₆H₄CH₂CONH₂(4) CH 25NHCH₂C₆H₅CO₂Et(3) CH 26 NHCH₂C₆H₅CO₂H(3) CH 27 NHCH₂C₆H₅CO₂Et(4) CH 28NHCH₂C₆H₅CO₂H(4) CH 29 NHCH₂C₆H₅CH₂CO₂Et(3) CH 30 NHCH₂C₆H₅CH₂CO₂H(3) CH31 NHCH₂C₆H₅CH₂CO₂Et(4) CH 32 NHCH₂C₆H₅CH₂CO₂H(4) CH 33NHCH₂C₆H₅OCH₂CO₂Et(3) CH 34 NHCH₂C₆H₅OCH₂CO₂H(3) CH 35NHCH₂C₆H₅OCH₂CO₂Et(4) CH 36 NHCH₂C₆H₅OCH₂CO₂H(4) CH 37NHCH₂C₆H₃(CN)₂(3,5) CH 38 NHCH₂C₆H₃(CN)₂(3,5) CH 39NHCH₂C₆H₃(CONH₂)₂(3,5) CH 40 NHCH₂C₆H₃(CONH₂)₂(3,5) CH 41NHCH₂C₆H₄—OCH₃(3) CH 42 NHCH₂C₆H₄—OCH₃(4) CH 43 NHCH₂C₆H₄C₆H₄CN(2,3, or4) CH 44 NHCH₂C₆H₄C₆H₄CONH₂(2,3, or 4) CH 45 NHCH₂C₆H₄C₆H₄CO₂Et(2,3, or4) CH 46 NHCH₂C₆H₄C₆H₄CO₂H(2,3, or 4) CH 47 NHCH₂C₆H₄—CH₃(3) CH 48NHCH₂C₆H₄—CH₃(4) CH

TABLE XIII

Ex. # X A 1 NHCH₂CH₂C₆H₅ N 2 NHCH₂C₆H₅ N 3 NHCH₂C₆H₄—Cl(3) N 4NHCH₂C₆H₄—Cl(4) N 5 NHCH₂C₆H₄—F(3) N 6 NHCH₂C₆H₄—F(4) N 7NHCH₂C₆H₄—CF₃(3) N 8 NHCH₂C₆H₄—CF₃(4) N 9 NHCH₂C₆H₄—NO₂(3) N 10NHCH₂C₆H₄—NO₂(4) N 11 NHCH₂C₆H₄—NHSO₂CH₃(3) N 12 NHCH₂C₆H₄—NHSO₂CH₃(4) N13 NHCH₂C₆H₄—CN(3) N 14 NHCH₂C₆H₄—CN(4) N 15 NHCH₂C₆H₄—CONH₂(3) N 16NHCH₂C₆H₄—CONH₂(4) N 17 NHCH₂C₆H₄—OCH₂CN(3) N 18 NHCH₂C₆H₄—OCH₂CN(4) N19 NHCH₂C₆H₄—OCH₂CONH₂(3) N 20 NHCH₂C₆H₄—OCH₂CONH₂(4) N 21NHCH₂C₆H₄CH₂CN(3) N 22 NHCH₂C₆H₄CH₂CN(4) N 23 NHCH₂C₆H₄CH₂CONH₂(3) N 24NHCH₂C₆H₄CH₂CONH₂(4) N 25 NHCH₂C₆H₅CO₂Et(3) N 26 NHCH₂C₆H₅CO₂H(3) N 27NHCH₂C₆H₅CO₂Et(4) N 28 NHCH₂C₆H₅CO₂H(4) N 29 NHCH₂C₆H₅CH₂CO₂Et(3) N 30NHCH₂C₆H₅CH₂CO₂H(3) N 31 NHCH₂C₆H₅CH₂CO₂Et(4) N 32 NHCH₂C₆H₅CH₂CO₂H(4) N33 NHCH₂C₆H₅OCH₂CO₂Et(3) N 34 NHCH₂C₆H₅OCH₂CO₂H(3) N 35NHCH₂C₆H₅OCH₂CO₂Et(4) N 36 NHCH₂C₆H₅OCH₂CO₂H(4) N 37 NHCH₂C₆H₃(CN)₂(3,5)N 38 NHCH₂C₆H₃(CN)₂(3,5) N 39 NHCH₂C₆H₃(CONH₂)₂(3,5) N 40NHCH₂C₆H₃(CONH₂)₂(3,5) N 41 NHCH₂C₆H₄—OCH₃(3) N 42 NHCH₂C₆H₄—OCH₃(4) N43 NHCH₂C₆H₄C₆H₄CN(2,3, or 4) N 44 NHCH₂C₆H₄C₆H₄CONH₂(2,3, or 4) N 45NHCH₂C₆H₄C₆H₄CO₂Et(2,3, or 4) N 46 NHCH₂C₆H₄C₆H₄CO₂H(2,3, or 4) N 47NHCH₂C₆H₄—CH₃(3) N 48 NHCH₂C₆H₄—CH₃(4) N

TABLE XIV

Ex. # X A 1. O(CH₂CH₂O)₂CH₂CH₂OH CH 2. O(CH₂CH₂O)₂CH₂CH₂OH N 3.O(CH₂CH₂O)₂CH₂CH₂OCH₃ CH 4. O(CH₂CH₂O)₂CH₂CH₂OCH₃ N 5.O(CH₂CH₂O)₃CH₂CH₂OH CH 6. O(CH₂CH₂O)₃CH₂CH₂OH N 7. O(CH₂CH₂O)₃CH₂CH₂OCH₃CH 8. O(CH₂CH₂O)₃CH₂CH₂OCH₃ N 9. O(CH₂CH₂O)₄CH₂CH₂OH CH 10.O(CH₂CH₂O)₄CH₂CH₂OH N 11. O(CH₂CH₂O)₄CH₂CH₂OCH₃ CH 12.O(CH₂CH₂O)₄CH₂CH₂OCH₃ N 13. O(CH₂CH₂O)₅CH₂CH₂OH CH 14.O(CH₂CH₂O)₅CH₂CH₂OH N 15. O(CH₂CH₂O)₅CH₂CH₂OCH₃ CH 16.O(CH₂CH₂O)₅CH₂CH₂OCH₃ N 17. O(CH₂CH₂O)₇CH₂CH₂OH CH 18.O(CH₂CH₂O)₇CH₂CH₂OH N 19. O(CH₂CH₂O)₇CH₂CH₂OCH₃ CH 20.O(CH₂CH₂O)₇CH₂CH₂OCH₃ N 21. O(CH₂CH₂O)₉CH₂CH₂OH CH 22.O(CH₂CH₂O)₉CH₂CH₂OH N 23. O(CH₂CH₂O)₉CH₂CH₂OCH₃ CH 24.O(CH₂CH₂O)₉CH₂CH₂OCH₃ N 25. O(CH₂CH₂O)₁₁CH₂CH₂OCH₃ CH 26.O(CH₂CH₂O)₁₁CH₂CH₂OCH₃ N

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

What is claimed is:
 1. A compound of formula I, or a stereoisomer or apharmaceutically acceptable salt thereof:

wherein: A is N; A¹ and A³ are CH; A² is CX; A⁴ is CY; R, at eachoccurrence, is independently selected from H and C₁₋₆ alkyl; R¹ isselected from H and C₁₋₆ alkyl; R² is selected from H and C₁₋₆ alkyl; Qis C═O; X is selected from H, OR³, NR³Z, OZ, SZ, SO₂OR³, SO₂NR³R⁴,CO₂R³, CONR³R⁴, PO(OR³)₂, (CH₂)_(m)CO₂R, (CH₂)_(m)CONR₂, NR—C₂₋₄alkenyl, NRSO₂CH₃, NR(CH₂)_(n)CO₂R, CH₂-aryl, O(CH₂)_(n)-biphenyl,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,O(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R,O(CH₂)_(n)-aryl-NRC₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-NR—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl O(CH₂)_(n)CN,O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²; X², at eachoccurrence, is independently selected from H, OR, C₁₋₄ alkyl, C₁₋₄alkyloxy, fluoro-C₁₋₄ alkyloxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen,CF₃, nitro, —CN, CON(R)₂, and SO₂N(R)C₁₋₄alkyl; Y is selected from H,OR³, NR³Z, OZ, SZ, SO₂OR³, SO₂NR³R⁴, CO₂R³, CONR³R⁴, PO(OR³)₂, CF₃,CON(R)₂, SO₂N(R)C₁₋₄alkyl and NHSO₂R; provided that when Q is C═O and A,A¹, A², A³, and A⁴ are other than N⁺—O⁻, then at least one of X and Y ispresent and is other than H, OH, OC₁₋₆ alkyl, OC₂₋₆ alkenyl, andaryl-C₁₋₆ alkyl-O—; Z, at each occurrence, is independently selectedfrom (CH₂)_(n)CO₂R³, CH₂CH═CHCO₂R³, (CH₂)_(n)CN, (CH₂)_(n)CONR³R⁴,CH₂CH═CHCN, CH₂CH═CHCON(R³)₂, (CH₂)_(n)PO(OR³)₂, (CH₂)_(n)SO₃R³, and(CH₂)_(n)N⁺(R³)₃G⁻; G⁻ is a counterion; R³, at each occurrence, isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and aryl-C₁₋₆alkyl-; R⁴, at each occurrence, is independently selected from H, C₁₋₆alkyl, phenyl, and CH(L)CO₂R³; L is selected from H, C₁₋₆ alkyl,—(CH₂)_(m)-phenyl, —(CH₂)_(n)—O—C₁₋₆ alkyl, and —(CH₂)_(n)—S—C₁₋₆ alkyl;m, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;n, at each occurrence, is independently selected from 1, 2, 3, and 4;and, p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and
 11. 2. Acompound of claim 1, wherein the compound is of formula Ia, or astereoisomer or a pharmaceutically acceptable salt thereof:

wherein: A is N; A¹ and A³ are CH; R, at each occurrence, isindependently selected from H and C₁₋₄ alkyl; R¹ is selected from H andC₁₋₄ alkyl; R² is selected from H and C₁₋₄ alkyl; X is selected from H,OR³, NR³Z, OZ, SZ, SO₂NR³R⁴, CONR³R⁴, (CH₂)_(m)CONR₂, NR—C₂₋₄ alkenyl,NRSO₂CH₃, CH₂-aryl, O(CH₂)_(n)-biphenyl,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)-biphenyl, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-aryl,O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl, NR(CH₂)_(n)-heteroaryl,O(CH₂)_(n)-aryl(CH₂)_(m)CN, O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-arylO(CH₂)_(n)CN, O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-aryl(CH₂)_(m)CN, NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-arylO(CH₂)_(n)CN, NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN,O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂,NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²; X², at eachoccurrence, is independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂, andSO₂N(R)C₁₋₄alkyl; Y is selected from SO₂OR³, CO₂R³, PO(OR³)₂,SO₂N(R)C₁₋₄alkyl, and NHSO₂R; Z is selected from (CH₂)_(n)CONR³R⁴,CH₂CH═CHCON(R³)₂, and (CH₂)_(n)N⁺(R³)₃G⁻; G⁻ is selected from Cl⁻ andBr⁻; R³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and benzyl; R⁴, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, phenyl, and CH(L)CO₂R³; and,L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.
 3. A compound of claim 1, wherein thecompound is of formula Ia, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein: A is N; A¹ and A³ are CH; R, at each occurrence, isindependently selected from H and C₁₋₄ alkyl; R¹ is selected from H andC₁₋₄ alkyl; R² is selected from H and C₁₋₄ alkyl; X is selected fromSO₂OR³, PO(OR³)₂, (CH₂)_(m)CO₂R, NR(CH₂)_(n)CO₂R,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂, O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R,O(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-NRC₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,NR(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, andO(CH₂CH₂O)_(p)CH₂CH₂OR³, where heteroaryl is a 5-12 membered ring systemconsisting of carbon atoms and from 1-4 heteroatoms selected from N, O,and S, and wherein aryl, heteroaryl, and biphenyl are substituted with1-2 X²; X², at each occurrence, is independently selected from H, OR,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN,CON(R)₂, and SO₂N(R)C₁₋₄alkyl; Y is selected from H, OW, NR³Z, OZ, SZ,SO₂NR³R⁴, CONR³R⁴, CF₃, CN, CON(R)₂, SO₂N(R)C₁₋₄alkyl, and NHSO₂R; Z isselected from (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂, and(CH₂)_(n)N⁺(R³)₃G⁻; G⁻ is selected from Cl⁻ and Br⁻; R³, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,and benzyl; R⁴, at each occurrence, is independently selected from H,C₁₋₄ alkyl, phenyl, and CH(L)CO₂R³; and, L is selected from H, CH₃,CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH₂SCH₃, phenyl, andbenzyl.
 4. A compound of claim 1, wherein the compound is of formula Ib,or a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein: A is N; A¹ is CH; R, at each occurrence, is independentlyselected from H and C₁₋₄ alkyl; R¹ is selected from H and C₁₋₄ alkyl; R²is selected from H and C₁₋₄ alkyl; X is selected from H, OR³, NR³Z, OZ,SZ, SO₂NR³R⁴, CONR³R⁴, (CH₂)_(m)CONR₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃,CH₂-aryl, O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²; X², at eachoccurrence, is independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂, andSO₂N(R)C₁₋₄-alkyl; Y is selected from SO₂OR³, CO₂R³, PO(OR³)₂,SO₂N(R)C₁₋₄alkyl and NHSO₂R; Z is selected from (CH₂)_(n)CONR³R⁴,CH₂CH═CHCON(R³)₂, and (CH₂)_(n)N±(R³)₃G⁻; G⁻ is selected from Cl⁻ andBr⁻; R³, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, and benzyl; R⁴, at each occurrence, isindependently selected from H, C₁₋₄ alkyl, phenyl, and CH(L)CO₂R³; and,L is selected from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂CH₂SCH₃, phenyl, and benzyl.
 5. A compound of claim 1, wherein thecompound is of formula Ib, or a stereoisomer or a pharmaceuticallyacceptable salt thereof:

wherein: A is N; A¹ is CH; R, at each occurrence, is independentlyselected from H and C₁₋₄ alkyl; R¹ is selected from H and C₁₋₄ alkyl; R²is selected from H and C₁₋₄ alkyl; X is selected from SO₂OR³, PO(OR³)₂,(CH₂)_(m)CO₂R, NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,O(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, O(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-aryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-arylO(CH₂)_(n)—PO(OR)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R,O(CH₂)_(n)-aryl-NRC₂₋₆ alkenyl-CO₂R,O(CH₂)_(n)-aryl-NR(CH₂)_(n)—PO(OR)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CO₂R,NR(CH₂)_(n)-aryl-C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-aryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-aryl-NR—C₂₋₆ alkenyl-CO₂R,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)PO(OR)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CO₂R,NR(CH₂)_(n)-aryl-O—C₂₋₆ alkenyl-CO₂R, NR(CH₂)_(n)-arylO(CH₂)_(n)PO(OR)₂,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, O(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroarylO(CH₂)_(n)—PO(OR)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, O(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CO₂R, NR(CH₂)_(n)-heteroaryl-C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl(CH₂)_(m)—PO(OR)₂,NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-NR—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)PO(OR)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CO₂R, NR(CH₂)_(n)-heteroaryl-O—C₂₋₆alkenyl-CO₂R, NR(CH₂)_(n)-heteroarylO(CH₂)_(n)PO(OR)₂, andO(CH₂CH₂O)_(p)CH₂CH₂OR³, where heteroaryl is a 5-12 membered ring systemconsisting of carbon atoms and from 1-4 heteroatoms selected from N, O,and S, and wherein aryl, heteroaryl, and biphenyl are substituted with1-2 X²; X², at each occurrence, is independently selected from H, OR,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN,CON(R)₂, and SO₂N(R)C₁₋₄alkyl; Y is selected from H, OW, NR³Z, OZ, SZ,SO₂NR³R⁴, CONR³R⁴, CF₃, CON(R)₂, SO₂N(R)C₁₋₄alkyl and NHSO₂R; Z isselected from (CH₂)_(n)CONR³R⁴, CH₂CH═CHCON(R³)₂, and(CH₂)_(n)N±(R³)₃G⁻; G⁻ is selected from Cl⁻ and Br⁻; R³, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,and benzyl; R⁴, at each occurrence, is independently selected from H,C₁₋₄ alkyl, phenyl, and CH(L)CO₂R³; and, L is selected from H, CH₃,CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH₂SCH₃, phenyl, andbenzyl.
 6. A compound of claim 1, wherein the compound is of formula Ic,or a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein: A is N; A¹ is CH; R, at each occurrence, is independentlyselected from H and C₁₋₄ alkyl; R¹ is selected from H and C₁₋₄ alkyl; R²is selected from H and C₁₋₄ alkyl; X is selected from NR³Z, SZ,SO₂NR³R⁴, CONR³R⁴, (CH₂)_(m)CONR₂, NR—C₂₋₄ alkenyl, NRSO₂CH₃, CH₂-aryl,O(CH₂)_(n)-biphenyl, O(CH₂)_(n)-biphenyl-(CH₂)_(m)CN,O(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-biphenyl,NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CN, NR(CH₂)_(n)-biphenyl-(CH₂)_(m)CON(R)₂,O(CH₂)_(n)-aryl, O(CH₂)_(n)-heteroaryl, NR(CH₂)_(n)-aryl,NR(CH₂)_(n)-heteroaryl, O(CH₂)_(n)-aryl(CH₂)_(m)CN,O(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-arylO(CH₂)_(n)CN,O(CH₂)_(n)-arylO(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-aryl(CH₂)_(m)CN,NR(CH₂)_(n)-aryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-NR(CH₂)_(n)CON(R)₂, NR(CH₂)_(n)-arylO(CH₂)_(n)CN,NR(CH₂)_(n)-aryl-O(CH₂)_(n)CON(R)₂, O(CH₂)_(n)-heteroaryl-(CH₂)_(m)CN,O(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CN, O(CH₂)_(n)-heteroarylO(CH₂)_(n)CON(R)₂,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CN,O(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CN,NR(CH₂)_(n)-heteroaryl(CH₂)_(m)CON(R)₂, NR(CH₂)_(n)heteroaryl-NR(CH₂)_(n)CN, NR(CH₂)_(n)-heteroaryl-NR(CH₂)_(n)CON(R)₂,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CN,NR(CH₂)_(n)-heteroaryl-O(CH₂)_(n)CON(R)₂, and O(CH₂CH₂O)_(p)CH₂CH₂OR³,where heteroaryl is a 5-12 membered ring system consisting of carbonatoms and from 1-4 heteroatoms selected from N, O, and S, and whereinaryl, heteroaryl, and biphenyl are substituted with 1-2 X²; X², at eachoccurrence, is independently selected from H, OR, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, CF₃, nitro, —CN, CON(R)₂, andSO₂N(R)C₁₋₄alkyl; Z is (CH₂)_(n)N⁺(R³)₃G⁻; G⁻ is selected from Cl⁻ andBr⁻; R³, at each occurrence, is independently selected from H, C₁₋₄alkyl, and benzyl; R⁴, at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, and CH(L)CO₂R³; and, L is selected from H, CH₃,CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH₂SCH₃, phenyl, andbenzyl.
 7. A compound of claim 1, wherein the compound is selected fromTable IV, or a stereoisomer or pharmaceutically acceptable salt thereof:TABLE IV

Ex. # X Y A A¹ A³ 1 CO₂Et H N CH CH 2 CO₂H H N CH CH 3 SO₃Et H N CH CH 4SO₃H H N CH CH 5 PO(OEt)₂ H N CH CH 6 PO(OH)₂ H N CH CH 7 NHCH₂CO₂Et H NCH CH 8 NHCH₂CO₂H H N CH CH 9 OCH₂CO₂Et H N CH CH 10 OCH₂CO₂H H N CH CH11 NHCH₂CH₂CO₂Et H N CH CH 12 NHCH₂CH₂CO₂H H N CH CH 13 OCH₂CH₂CO₂Et H NCH CH 14 OCH₂CH₂CO₂H H N CH CH 15 NHCH₂CH═CHCO₂Et H N CH CH 16NHCH₂CH═CHCO₂H H N CH CH 17 OCH₂CH═CHCO₂Et H N CH CH 18 OCH₂CH═CHCO₂H HN CH CH 19 OCH₂CH₂PO(OEt)₂ H N CH CH 20 OCH₂CH₂PO(OH)₂ H N CH CH 21OCH₂CH₂N(CH₃)₂ H N CH CH 22 OCH₂CH₂N⁺(CH₃)₃Cl⁻ H N CH CH 23 SO₂NHEt H NCH CH 24 CONHCH(CH₃)CO₂Et H N CH CH 25 CONHCH(CH₃)CO₂H H N CH CH 26CONHCH(CH₂C₆H₅)CO₂Et H N CH CH 27 CONHCH(CH₂C₆H₅)CO₂H H N CH CH 28NHCH₂CONH₂ H N CH CH 29 NHCH₂CH₂CONH₂ H N CH CH 30 OCH₂CONH₂ H N CH CH31 OCH₂CH₂CONH₂ H N CH  CH.


8. A compound of claim 1, wherein the compound is selected from TableXI, or a stereoisomer or pharmaceutically acceptable salt thereof: TABLEXI

Ex. # X A 5 OCH₂C₆H₄—F(3) N 6 OCH₂C₆H₄—F(4) N 7 OCH₂C₆H₄—CF₃(3) N 8OCH₂C₆H₄—CF₃(4) N 9 OCH₂C₆H₄—NO₂(3) N 10 OCH₂C₆H₄—NO₂(4) N 11OCH₂C₆H₄—NHSO₂CH₃(3) N 12 OCH₂C₆H₄—NHSO₂CH₃(4) N 13 OCH₂C₆H₄—CN(3) N 14OCH₂C₆H₄—CN(4) N 15 OCH₂C₆H₄—CONH₂(3) N 16 OCH₂C₆H₄—CONH₂(4) N 17OCH₂C₆H₄—OCH₂CN(3) N 18 OCH₂C₆H₄—OCH₂CN(4) N 19 OCH₂C₆H₄—OCH₂CONH₂(3) N20 OCH₂C₆H₄—OCH₂CONH₂(4) N 21 OCH₂C₆H₄CH₂CN(3) N 22 OCH₂C₆H₄CH₂CN(4) N23 OCH₂C₆H₄CH₂CONH₂(3) N 24 OCH₂C₆H₄CH₂CONH₂(4) N 25 OCH₂C₆H₄CO₂Et(3) N26 OCH₂C₆H₄CO₂H(3) N 27 OCH₂C₆H₄CO₂Et(4) N 28 OCH₂C₆H₄CO₂H(4) N 29OCH₂C₆H₄CH₂CO₂Et(3) N 30 OCH₂C₆H₄CH₂CO₂H(3) N 31 OCH₂C₆H₄CH₂CO₂Et(4) N32 OCH₂C₆H₄CH₂CO₂H(4) N 33 OCH₂C₆H₄OCH₂CO₂Et(3) N 34 OCH₂C₆H₄OCH₂CO₂H(3)N 35 OCH₂C₆H₄OCH₂CO₂Et(4) N 36 OCH₂C₆H₄OCH₂CO₂H(4) N 37OCH₂C₆H₃(CN)₂(3,5) N 38 OCH₂C₆H₃(CN)₂(3,5) N 39 OCH₂C₆H₃(CONH₂)₂(3,5) N40 OCH₂C₆H₃(CONH₂)₂(3,5) N 41 OCH₂C₆H₄—OCH₃(3) N 42 OCH₂C₆H₄—OCH₃(4) N43

N 43′

N 43″

N 43a

N 43a′

N 43a″

N 43b

N 43b′

N 43b″

N 44

N 44′

N 44″

N 44a

N 44a′

N 44a″

N 44b

N 44b′

N 44b″

N 45

N 45′

N 45″

N 45a

N 45a′

N 45a″

N 45b

N 45b′

N 45b″

N 46

N 46′

N 46″

N 46a

N 46a′

N 46a″

N 46b

N 46b′

N 46b″

N 47 OCH₂C₆H₄—CH₃(3) N 48 OCH₂C₆H₄—CH₃(4) N

wherein the number or numbers in the parentheses indicate the point ofattachment of the substituent on the C₆H₄ or the C₆H₃ ring.
 9. Acompound of claim 1, wherein the compound is selected from Table XIII,or a stereoisomer or pharmaceutically acceptable salt thereof: TABLEXIII

Ex. # X A 1 NHCH₂CH₂C₆H₅ N 2 NHCH₂C₆H₅ N 3 NHCH₂C₆H₄—Cl(3) N 4NHCH₂C₆H₄—Cl(4) N 5 NHCH₂C₆H₄—F(3) N 6 NHCH₂C₆H₄—F(4) N 7NHCH₂C₆H₄—CF₃(3) N 8 NHCH₂C₆H₄—CF₃(4) N 9 NHCH₂C₆H₄—NO₂(3) N 10NHCH₂C₆H₄—NO₂(4) N 11 NHCH₂C₆H₄—NHSO₂CH₃(3) N 12 NHCH₂C₆H₄—NHSO₂CH₃(4) N13 NHCH₂C₆H₄—CN(3) N 14 NHCH₂C₆H₄—CN(4) N 15 NHCH₂C₆H₄—CONH₂(3) N 16NHCH₂C₆H₄—CONH₂(4) N 17 NHCH₂C₆H₄—OCH₂CN(3) N 18 NHCH₂C₆H₄—OCH₂CN(4) N19 NHCH₂C₆H₄—OCH₂CONH₂(3) N 20 NHCH₂C₆H₄—OCH₂CONH₂(4) N 21NHCH₂C₆H₄CH₂CN(3) N 22 NHCH₂C₆H₄CH₂CN(4) N 23 NHCH₂C₆H₄CH₂CONH₂(3) N 24NHCH₂C₆H₄CH₂CONH₂(4) N 25 NHCH₂C₆H₄CO₂Et(3) N 26 NHCH₂C₆H₄CO₂H(3) N 27NHCH₂C₆H₄CO₂Et(4) N 28 NHCH₂C₆H₄CO₂H(4) N 29 NHCH₂C₆H₄CH₂CO₂Et(3) N 30NHCH₂C₆H₄CH₂CO₂H(3) N 31 NHCH₂C₆H₄CH₂CO₂Et(4) N 32 NHCH₂C₆H₄CH₂CO₂H(4) N33 NHCH₂C₆H₄OCH₂CO₂Et(3) N 34 NHCH₂C₆H₄OCH₂CO₂H(3) N 35NHCH₂C₆H₄OCH₂CO₂Et(4) N 36 NHCH₂C₆H₄OCH₂CO₂H(4) N 37 NHCH₂C₆H₃(CN)₂(3,5)N 38 NHCH₂C₆H₃(CN)₂(3,5) N 39 NHCH₂C₆H₃(CONH₂)₂(3,5) N 40NHCH₂C₆H₃(CONH₂)₂(3,5) N 41 NHCH₂C₆H₄—OCH₃(3) N 42 NHCH₂C₆H₄—OCH₃(4) N43

N 43′

N 43″

N 43a

N 43a′

N 43a″

N 43b

N 43b′

N 43b″

N 44

N 44′

N 44″

N 44a

N 44a′

N 44a″

N 44b

N 44b′

N 44b″

N 45

N 45′

N 45″

N 45a

N 45a′

N 45a″

N 45b

N 45b′

N 45b″

N 46

N 46′

N 46″

N 46a

N 46a′

N 46a″

N 46b

N 46b′

N 46b″

N 47 NHCH₂C₆H₄—CH₃(3) N 48 NHCH₂C₆H₄—CH₃(4) N

wherein the number or numbers in the parentheses indicate the point ofattachment of the sub stituent on the C₆H₄ or the C₆H₃ ring.
 10. Acompound of claim 1, wherein the compound is selected from Table XIV, ora stereoisomer or pharmaceutically acceptable salt thereof: TABLE XIV

Ex # X A
 1. O(CH₂CH₂O)₂CH₂CH₂OH N
 2. O(CH₂CH₂O)₂CH₂CH₂OCH₃ N 3.O(CH₂CH₂O)₃CH₂CH₂OH N
 4. O(CH₂CH₂O)₃CH₂CH₂OCH₃ N
 5. O(CH₂CH₂O)₄CH₂CH₂OHN
 6. O(CH₂CH₂O)₄CH₂CH₂OCH₃ N
 7. O(CH₂CH₂O)₅CH₂CH₂OH N 8.O(CH₂CH₂O)₅CH₂CH₂OCH₃ N
 9. O(CH₂CH₂O)₇CH₂CH₂OH N 10.O(CH₂CH₂O)₇CH₂CH₂OCH₃ N
 11. O(CH₂CH₂O)₉CH₂CH₂OH N 12.O(CH₂CH₂O)₉CH₂CH₂OCH₃ N
 13. O(CH₂CH₂O)₁₁CH₂CH₂OCH₃ N


11. A pharmaceutical composition, comprising: a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical composition, comprising: atherapeutically effective amount of a compound of claim 2 and apharmaceutically acceptable carrier.
 13. A pharmaceutical composition,comprising: a therapeutically effective amount of a compound of claim 3and a pharmaceutically acceptable carrier.
 14. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound of claim 4 and a pharmaceutically acceptable carrier.
 15. Apharmaceutical composition, comprising: a therapeutically effectiveamount of a compound of claim 5 and a pharmaceutically acceptablecarrier.
 16. A pharmaceutical composition, comprising: a therapeuticallyeffective amount of a compound of claim 6 and a pharmaceuticallyacceptable carrier.
 17. A pharmaceutical composition, comprising: atherapeutically effective amount of a compound of claim 6 and apharmaceutically acceptable carrier.
 18. A pharmaceutical composition,comprising: a therapeutically effective amount of a compound of claim 8and a pharmaceutically acceptable carrier.
 19. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound of claim 9 and a pharmaceutically acceptable carrier.
 20. Apharmaceutical composition, comprising: a therapeutically effectiveamount of a compound of claim 10 and a pharmaceutically acceptablecarrier.